AU2011242712B2 - Process of producing cycloalkylcarboxamido-indole compounds - Google Patents

Process of producing cycloalkylcarboxamido-indole compounds Download PDF

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AU2011242712B2
AU2011242712B2 AU2011242712A AU2011242712A AU2011242712B2 AU 2011242712 B2 AU2011242712 B2 AU 2011242712B2 AU 2011242712 A AU2011242712 A AU 2011242712A AU 2011242712 A AU2011242712 A AU 2011242712A AU 2011242712 B2 AU2011242712 B2 AU 2011242712B2
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compound
formula
aliphatic
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hal
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Daniel T. Belmont
Cristian Harrison
Robert Michael Hughes
Young Chun Jung
Elaine Chungmin Lee
Benjamin Joseph Littler
Peter Jamison Rose
David Andrew Siesel
Gerald J. Tanoury
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Vertex Pharmaceuticals Inc
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Abstract

The present invention features processes for preparing compounds, such as (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2- (1 -hydroxy-2-methylpropan-2-yl)- 1H-indol-5 -yl)cyclopropanecarboxamide (Compound 1 ), useful for treating CFTR mediated diseases such as cystic fibrosis.

Description

WO 2011/133751 PCT/US2011/033396 PROCESS OF PRODUCING CYCLOALKYLCARBOXAMIDO-INDOLE COMPOUNDS CROSS REFERENCE TO RELATED APPLICATIONS [0011 This application claims priority to United States provisional patent application serial numbers 61/333,870, filed May 12, 2010; 61/327,095, filed April 22, 2010; 61/327,057, filed April 22, 2010; 61/329,493, filed April 29, 2010; 61/327,091, filed April 22, 2010; 61/329,510, filed April 29, 2010; 61/327,099, filed April 22, 2010; and 61/329,500, filed April 29, 2010, the entire contents of all applications are incorporated herein by reference. TECHNICAL FIELD OF THE INVENTION [002] The present invention features processes for preparing compounds useful for treating CFTR mediated diseases such as cystic fibrosis. BACKGROUND OF THE INVENTION [0031 CFTR is a cAMP/ATP-mediated anion channel that is expressed in a variety of cells types, including absorptive and secretory epithelia cells, where it regulates anion flux across the membrane, as well as the activity of other ion channels and proteins. In epithelia cells, normal functioning of CFTR is critical for the maintenance of electrolyte transport throughout the body, including respiratory and digestive tissue. CFTR is composed of approximately 1480 amino acids that encode a protein made up of a tandem repeat of transmembrane domains, each containing six transmembrane helices and a nucleotide binding domain. The two transmembrane domains are linked by a large, polar, regulatory (R)-domain with multiple phosphorylation sites that regulate channel activity and cellular trafficking. [0041 The gene encoding CFTR has been identified and sequenced (See Gregory, R. J. et al. (1990) Nature 347:382-386; Rich, D. P. et al. (1990) Nature 347:358-362), (Riordan, J. R. et al. (1989) Science 245:1066-1073). A defect in this gene causes mutations in CFTR resulting in cystic fibrosis ("CF"), the most common fatal genetic disease in humans. Cystic fibrosis affects approximately one in every 2,500 infants in the United States. Within the -1- WO 2011/133751 PCT/US20111/033396 general United States population, up to 10 million people carry a single copy of the defective gene without apparent ill effects. In contrast, individuals with two copies of the CF associated gene suffer from the debilitating and fatal effects of CF, including chronic lung disease. [005] In patients with cystic fibrosis, mutations in CFTR endogenously expressed in respiratory epithelia leads to reduced apical anion secretion causing an imbalance in ion and fluid transport. The resulting decrease in anion transport contributes to enhanced mucus accumulation in the lung and the accompanying microbial infections that ultimately cause death in CF patients. In addition to respiratory disease, CF patients typically suffer from gastrointestinal problems and pancreatic insufficiency that, if left untreated, results in death. In addition, the majority of males with cystic fibrosis are infertile and fertility is decreased among females with cystic fibrosis. In contrast to the severe effects of two copies of the CF associated gene, individuals with a single copy of the CF associated gene exhibit increased resistance to cholera and to dehydration resulting from diarrhea - perhaps explaining the relatively high frequency of the CF gene within the population. [006] Sequence analysis of the CFTR gene of CF chromosomes has revealed a variety of disease causing mutations (Cutting, G. R. et al. (1990) Nature 346:366-369; Dean, M. et al. (1990) Cell 61:863:870; and Kerem, B-S. et al. (1989) Science 245:1073-1080; Kerem, B S et al. (1990) Proc. Natl. Acad. Sci. USA 87:8447-8451). To date, > 1000 disease causing mutations in the CF gene have been identified (http://www.ge net.sickkids.on.ca/cftr/). The most prevalent mutation is a deletion of phenylalanine at position 508 of the CFTR amino acid sequence, and is commonly referred to as AF508-CFTR. This mutation occurs in approximately 70% of the cases of cystic fibrosis and is associated with a severe disease. Other mutations include the RI 17H and G551D. [0071 The deletion of residue 508 in AF508-CFTR prevents the nascent protein from folding correctly. This results in the inability of the mutant protein to exit the ER, and traffic to the plasma membrane. As a result, the number of channels present in the membrane is far less than observed in cells expressing wild-type CFTR. In addition to impaired trafficking, the mutation results in defective channel gating. Together, the reduced number of channels in the membrane and the defective gating lead to reduced anion transport across epithelia leading to defective ion and fluid transport. (Quinton, P. M. (1990), FASEB J. 4: 2709-2727). Studies -2- WO 2011/133751 PCT/US2011/033396 have shown, however, that the reduced numbers of AF508-CFTR in the membrane are functional, albeit less than wild-type CFTR. (Dalemans et al (1991), Nature Lond. 354: 526 528; Denning et al., supra; Pasyk and Foskett (1995), J. Cell. Biochem. 270: 12347-50). In addition to AF508-CFTR, other disease causing mutations in CFTR that result in defective trafficking, synthesis, and/or channel gatir g could be up- or down-regulated to alter anion secretion and modify disease progression and/or severity. [0081 Although CFTR transports a var iety of molecules in addition to anions, it is clear that this role (the transport of anions" repres ents one element in an important mechanism of transporting ions and water across the epitheliumn. The other elements include the epithelial Na* channel, ENaC, Na*/2Cl-/K co-transporter, Na*-K'-ATPase pump and the basolateral membrane K* channels, that are responsib le for the uptake of chloride into the cell. [0091 These elements work together to achieve directional transport across the epithelium via their selective expression and localization within the cell. Chloride absorption takes place by the coordinated activity of ENaC and CFTR present on the apical membrane and the Na*-Kt-ATPase pump and Cl- channels expressed on the basolateral surface of the cell. Secondary active transport of chloride from the himinal side leads to the accumulation of intracellular chloride, which can then pass vely leave the cell via Cl- channels, resulting in a vectorial transport. Arrangement of Na*/2C-/K co-transporter, Nat-K'-ATPase pump and the basolateral membrane K channels on the basolatiral surface and CFTR on the luminal side coordinate the secretion of chloride via Cf TR on the luminal side. Because water is probably never actively transported itself, its flow across epithelia depends on tiny transepithelial osmotic gradients generated by the bulk flow of sodium and chloride. [001Q] As discussed above, it is I:elieved that the deletion of residue 508 in AF508 CFTR prevents the nascent protein from folding correctly, resulting in the inability of this mutant protein to exit the ER, and traffic to the plasma membrane. As a result, insufficient amounts of the mature protein are present at the F lasma membrane and chloride transport within epithelial tissues is significantly reduced. In fact, this cellular phenomenon of defective ER processing of ABC transporters by the ER machinery, has been shown to be the underlying basis not only for CF disease, but for a. wide rang. of other isolated and inherited diseases. The two ways that the ER machinery can malfunction is either by loss of coupling to ER export of 3 4 proteins leading to degradation, or by the ER accumulation of these defective/misfolded proteins [Aridor M, et al., Nature Med., 5(7), pp 745- 751 (1999); Shastry, B.S., et al., Neurochem. International, 43, pp 1-7 (2003); Rutishauser, J., et al., Swiss Med Wkly, 132, pp 211-222 (2002); Morello, JP et al., TIPS, 21, pp. 466- 469 (2000); Bross P., et al., 5 Human Mut., 14, pp. 186-198 (1999)]. [0011] (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6 fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide is disclosed in US published patent application US20090131492 (said publication being incorporated herein by reference in its entirety) as a modulator of CFTR activity and thus 10 useful in treating CFTR-mediated diseases such as cystic fibrosis. There remains, however, a need for economical processes for the preparation of the cycloalkylcarboxamido-indole compounds described herein. SUMMARY OF THE INVENTION [0012] As described herein, the present invention provides processes for preparing 15 CFTR correctors useful in the treatment of CFTR mediated diseases, such as cystic fibrosis. Such compounds include (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1 (2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5 yl)cyclopropanecarboxamide (hereinafter "Compound 1") which has the structure below: H Fo I O OH SOH OH 20 Compound 1. [0013] Compound 1 and pharmaceutically acceptable compositions thereof are useful for treating or lessening the severity of CFTR mediated diseases such as, for example, cystic fibrosis. Compound 1 may exist in several different solid forms such as substantially crystalline forms or amorphous forms. 25 4a [0013a] A first aspect of the invention provides for a method for preparing a compound of formula I: Gl X 5 wherein, independently for each occurrence: ring A is ;
R
1 is independently selected from -Ri, -OR', -N(R') 2 , -NO 2 , halogen, -CN, -C_ 4 haloalkyl,
-C
1
_
4 haloalkoxy, -C(O)N(R ) 2 , -NRJC(O)Rj, -SORJ, -SO 2 RJ, -SO 2
N(R)
2 ,
-NRSO
2 RJ, -COR, -CO 2 RJ, -NRJSO 2
N(RJ)
2 , -COCORJ; 10 R is hydrogen or C 1
_
6 aliphatic; X is CN or CO 2 R; R is C1_6 aliphatic or aryl; and m is an integer from 0 to 3 inclusive; comprising the steps of 15 a) reacting a compound of formula IA in a first organic solvent
(R
1 ),m Hal IA wherein, independently for each occurrence: ring A is ; 20 R 1 is independently selected from -Ri, -ORJ, -N(RJ) 2 , -NO 2 , halogen, -CN, -C1_ 4 haloalkyl, -C1_ 4 haloalkoxy, -C(O)N(R ) 2 , -NRJC(O)Rj, -SORJ, -SO 2 RJ, -SO 2
N(R)
2 ,
-NRSO
2 RJ, -COR, -CO 2 RJ, -NRJSO 2
N(RJ)
2 , -COCORJ; R is hydrogen or C1_6 aliphatic; m is an integer from 0 to 3 inclusive; and 25 Hal is a halide; 4b with a compound of formula IB: 0 IB wherein RI is hydrogen or C1_6 aliphatic, to form a compound of formula IC: (R1)m A OR' 5 X IC wherein, independently for each occurrence: ring A is ;
R
1 is independently selected from -Ri, -OR', -N(R') 2 , -NO 2 , halogen, -CN, -C 1
_
4 haloalkyl, 10 -C1_ 4 haloalkoxy, -C(O)N(R ) 2 , -NRJC(O)Rj, -SORJ, -SO 2 RJ, -SO 2
N(R)
2 ,
-NRSO
2 RJ, -COR, -CO 2 RJ, -NRJSO 2
N(RJ)
2 , -COCORJ; R is hydrogen or C 1
_
6 aliphatic; X is CN or CO 2 R; R is C1_6 aliphatic or aryl; and 15 m is an integer from 0 to 3 inclusive; and b) removing the -CO 2 R group from compound IC in a second organic solvent to form a compound of formula I. [0013b] A second aspect of the invention provides for a method for preparing a compound of formula II: (R1)m A 0 Hal 20
II
4c wherein, independently for each occurrence: ring A is ; Hal is a halide;
R
1 is independently selected from -Ri, -OR, -N(RJ) 2 , -NO 2 , halogen, -CN, -C1_ 4 haloalkyl, 5 -C1_ 4 haloalkoxy, -C(O)N(R ) 2 , -NRJC(O)Rj, -SORJ, -SO 2 RJ, -SO 2
N(R)
2 ,
-NRSO
2 RJ, -COR, -CO 2 RJ, -NRJSO 2
N(RJ)
2 , -COCORJ; R is hydrogen or C1_6 aliphatic; m is an integer from 0 to 3 inclusive; and n is an integer from 1 to 4 inclusive; 10 comprising the steps of a) reacting a compound of formula IIA in a first organic solvent
(R
1 )m Hal IIA wherein, independently for each occurrence: 15 ring A is ;
R
1 is independently selected from -Ri, -ORJ, -N(RJ) 2 , -NO 2 , halogen, -CN, -C1_ 4 haloalkyl,
-C
1
_
4 haloalkoxy, -C(O)N(R ) 2 , -NRJC(O)Rj, -SORJ, -SO 2 RJ, -SO 2
N(R)
2 ,
-NRSO
2 RJ, -COR, -CO 2 RJ, -NRJSO 2
N(RJ)
2 , -COCORJ; R is hydrogen or C1_6 aliphatic; 20 m is an integer from 0 to 3 inclusive; and Hal is a halide; with a compound of formula IIB: 0 JIB 25 wherein X is CN or CO 2 R; R is C1_6 aliphatic or aryl; and 4d RI is hydrogen or C 1
_
6 aliphatic, to form a compound of formula IIC: (R1)m A 0 G l OR' X x IIC wherein, independently for each occurrence: 5 ring A is ;
R
1 is independently selected from -Ri, -OR', -N(R') 2 , -NO 2 , halogen, -CN, -C1_ 4 haloalkyl,
-C
1
_
4 haloalkoxy, -C(O)N(R ) 2 , -NRJC(O)Rj, -SORJ, -SO 2 RJ, -SO 2
N(R)
2 ,
-NRSO
2 RJ, -COR, -CO 2 RJ, -NRJSO 2
N(RJ)
2 , -COCORJ; R is hydrogen or C1_6 aliphatic; 10 X is CN or CO 2 R; R is C1_6 aliphatic or aryl; and m is an integer from 0 to 3 inclusive; b) removing the -CO 2 RJ group from compound IIC in a second organic solvent to form a compound of formula I: (R1)m Al 15x wherein, independently for each occurrence: ring A is ;
R
1 is independently selected from -Ri, -ORJ, -N(RJ) 2 , -NO 2 , halogen, -CN, -C1_ 4 haloalkyl, 20 -C1_ 4 haloalkoxy, -C(O)N(R ) 2 , -NRJC(O)Rj, -SOR, -SO 2 R, -SO 2
N(R)
2 , NRJSO 2 R, -CORJ, -CO 2 R, -NRSO 2
N(R)
2 , -COCORJ; R is hydrogen or C1_6 aliphatic; X is CN or CO 2
R;
4e R is C 1
_
6 aliphatic or aryl; and m is an integer from 0 to 3 inclusive; c) reacting a compound of formula I with a compound of formula IID in the presence of a base: Hal Hal 5 q IID wherein, independently for each occurrence: Hal is a halide; and q is an integer from 0 to 3 inclusive; to produce a compound of formula IIE: (R1)m x 10 n IIE wherein, independently for each occurrence: ring A is ;
R
1 is independently selected from -Ri, -OR', -N(R') 2 , -NO 2 , halogen, -CN, -C1_ 4 haloalkyl, 15 -C1_ 4 haloalkoxy, -C(O)N(R ) 2 , -NRJC(O)Rj, -SOR, -SO 2 R, -SO 2
N(R)
2 , NRJSO 2 R, -CORJ, -CO 2 R, -NRSO 2
N(R)
2 , -COCORJ; R is hydrogen or C 1
_
6 aliphatic; m is an integer from 0 to 3 inclusive; X is CN or CO 2 R; 20 R is C 1
_
6 aliphatic or aryl; and n is an integer from 1 to 4 inclusive; 4f d) sequentially reacting a compound of formula IE with a hydroxide base and acid to form a compound of formula IIF: (R1)m Al| OH n IIF 5 wherein, independently for each occurrence: ring A is ;
R
1 is independently selected from -Ri, -OR', -N(R') 2 , -NO 2 , halogen, -CN, -C1_ 4 haloalkyl,
-C
1
_
4 haloalkoxy, -C(O)N(R ) 2 , -NRJC(O)Rj, -SORJ, -SO 2 RJ, -SO 2
N(R)
2 ,
-NRSO
2 RJ, -COR, -CO 2 RJ, -NRJSO 2
N(RJ)
2 , -COCORJ; 10 R is hydrogen or C1_6 aliphatic; m is an integer from 0 to 3 inclusive; and n is an integer from 1 to 4 inclusive; and e) reacting a compound of formula IIF with a halogenating agent in a third organic solvent to form a compound of formula II. 15 [0013c] A third aspect of the invention provides for a compound of Formula I prepared according to the process of the first aspect of the invention. [0013d] A fourth aspect of the invention provides for a compound of Formula II prepared according to the process of the second aspect of the invention.
WO 2011/133751 PCT/US20111/033396 DETAILED DESCRIPTION OF THE INVENTION [0014] Definitions [0015] As used herein, the following definitions shall apply unless otherwise indicated. [0016] The term "CFTR" as used herein means cystic fibrosis transmembrane conductance regulator or a mutation thereof capable of regulator activity, including, but not limited to, AF508 CFTR and G551D CFTR (see, e.g., http://www.genet.sickkids.on.ca/cftr/, for CFTR mutations). [0017] The term "modulating" as used herein means increasing or decreasing, e.g. activity, by a measurable amount. [0018] The term "chemically stable", as used herein, means that the solid form of Compound 1 does not decompose into one or more different chemical compounds when subjected to specified conditions, e.g., 40 0 C/75 % relative humidity, for a specific period of time. e.g. 1 day, 2 days, 3 days, 1 week, 2 weeks, or longer. In some embodiments, less than 25% of the solid form of Compound 1 decomposes, in some embodiments, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 3%, less than about 1%, less than about 0.50% of the form of Compound 1 decomposes under the conditions specified. In some embodiments, no detectable amount of the solid form of Compound 1 decomposes. [0019] The term "physically stable", as used herein, means that the solid form of Compound 1 does not change into one or more different physical forms of Compound 1 (e.g. different solid forms as measured by XRPD, DSC, etc.) when subjected to specific conditions, e.g., 40 0 C/75 % relative humidity, for a specific period of time. e.g. 1 day, 2 days, 3 days, 1 week, 2 weeks, or longer. In some embodiments, less than 25% of the solid form of Compound 1 changes into one or more different physical forms when subjected to specified conditions. In some embodiments, less than about 2 0%, less than about 150%, less than about 10%, less than about 5%, less than about 3 %, less than about 1%, less than about 0.5% of the solid form of Compound 1 changes into one or more different physical forms of Compound 1 when subjected to specified conditions. In some embodiments, no detectable amount of the solid form of Compound I changes into one or more physically different solid forms of Compound 1. -5- WO 2011/133751 PCT/US20111/033396 [0020] As used herein, the terms "about" and "approximately", when used in connection with doses, amounts, or weight percent of ingredients of a composition or a dosage form, mean a dose, amount, or weight percent that is recognized by one of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percent. Specifically the term "about" or "approximately" means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" means within 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2 %, l%, 0.5%, 0.1%, or 0.05% of a given value or range. [0021] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. All tautomeric forms of the Compound 1 are included herein. For example, Compound 1 may exist as tautomers, both of which are included herein: F F OH F 0F OH OH OH [0022] Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, Compound 1, wherein one or more hydrogen atoms are replaced deuterium or tritium, or one or more carbon atoms are replaced by a 1 3 C- or 4 C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, probes in biological assays, or compounds with improved therapeutic profile. -6- WO 2011/133751 PCT/US20111/033396 [0023] The term "protecting group," abbreviated as P, as used herein refers to any chemical group introduced into a molecule by chemical modification of a functional group in order to obtain chemoselectivity in a subsequent chemical reaction. Non-limiting examples of alcohol protecting groups include acetyl (Ac), benzoyl (Bz), benzyl (Bn), 3 methoxyethoxymethyl ether (MEM), dimethoxytrityl (DMT), methoxymethyl ether (MOM), methoxytrityl (MMT), p-methoxybenzyl ether (PMB), pivaloyl (Piv), tetrahydropyranyl (THP), trityl (Tr), and trimethylsilyl (TMS). In one embodiment, the protecting group is Bn which has the structure -CH 2
C
6
H
5 . [0024] The abbreviation "DCM" stands for dichloromethane. The abbreviation "IPA" stands for isopropyl alcohol. The abbreviation "DMSO" stands for dimethylsulfoxide. The abbreviation "MTBE" stands for methyl t-butyl ether. The abbreviation "THF" stands for tetrahydrofuran. The abbreviation "TEA" stands for triethylamine. The abbreviation "dba" as in Pd(dba) 2 stands for dibenzylidencacetone. The abbreviation "dppf' as in Pd(dppf)C1 2 stands for stands for 1,1'-bis(diphenylphosphino) ferrocene. [0025] In one aspect, the invention features a method for preparing a compound of formula I: (R1)m Al x wherein, independently for each occurrence: ring A is a fused cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring; Ri is independently selected from -RW, -OR, -N(R)2, -NO 2 , halogen, -CN, -C 1
_
4 haloalkyl, -C1_ 4 haloalkoxy, -C(O)N(R 3
)
2 , -NRC(O)R, -SOR, -SO 2 R', -SO 2 N(R )2, -NRSO 2 R, COR, -CO 2
R
3 , -NRSO 2
N(R)
2 , -COCOR'; R is hydrogen or C1_ 6 aliphatic; X is CN or CO 2 R; R is C1_ 6 aliphatic or aryl; and -7- WO 2011/133751 PCT/US20111/033396 m is an integer from 0 to 3 inclusive; comprising the steps of a) reacting a compound of formula IA in a first organic solvent (Ri)m Hal IA wherein, independently for each occurrence: ring A is a fused cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring;
R
1 is independently selected from -Ri, -OR, -N(R) 2 , -NO 2 , halogen, -CN, -C1_ 4 haloalkyl, -C1_ 4 haloalkoxy, -C(O)N(R!) 2 , -NR 2 C(O)R', -SOR', -S0 2 R,
-SO
2
N(R)
2 , -NR'SO 2 RJ, -COR', -CO 2 R, -NRSO 2
N(R)
2 , -COCOR; R is hydrogen or C 1
-
6 aliphatic; m is an integer from 0 to 3 inclusive; and Hal is a halide; with a compound of formula IB: 0 IAO RI IB wherein R is hydrogen or C1_6 aliphatic, to form a compound of formula IC: (Ri)m A0 ORJ x IC wherein, independently for each occurrence: -8- WO 2011/133751 PCT/US20111/033396 ring A is a fused cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring;
R
1 is independently selected from -R, -OR, -N(R) 2 , -NO 2 , halogen, -CN, -C1_ 4 haloalkyl, -C1_ 4 haloalkoxy, -C(O)N(R) 2 , -NR'C(O)R', -SOR', -S0 2 R,
-SO
2
N(R)
2 , -NR'SO 2 R', -CORJ, -CO 2 R, -NWSO 2
N(R)
2 , -COCOR; R is hydrogen or C1-6 aliphatic; X is CN or CO 2 R; R is R is C 1
_
6 aliphatic or aryl; and m is an integer from 0 to 3 inclusive; and b) removing the -CO 2 R group from compound IC in a second organic solvent to form a compound of formula I. [0026] In another embodiment, the invention features the above method wherein ring A is a fused heterocycloalkyl or heteroaryl. In another embodiment, ring A is selected from F><O 00: FO CN. In another embodiment, X is CO 2 Et. [0028] In another embodiment, the invention features the above method wherein m is 0. [00291 In another embodiment, the invention features the above method wherein R is a
C
1 _ aliphatic. In another embodiment, W is -CH 2 CH3. [00301 In another embodiment, the invention features the above method wherein Hal is Br. -9- WO 2011/133751 PCT/US20111/033396 [0031] In another embodiment, the invention features the above method wherein the first organic solvent is an aprotic solvent. In another embodiment, the first organic solvent is selected from 1,2-dimethoxyethane, dioxane, acetonitrile, toluene, benzene, xylenes, methyl t butyl ether, methyl ethyl ketone, methyl isobutyl ketone, acetone, NN-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, ethyl acetate, dichloromethane, or dimethylsulfoxide. In another embodiment, the first organic solvent is selected from acetonitrile, toluene, benzene, or xylenes. In another embodiment, the first organic solvent is toluene. [0032] In another embodiment, the invention features the above method wherein step a) is carried out in the presence of a transition metal catalyst. In another embodiment, step a) is carried out in the presence of a palladium catalyst. In another embodiment, step a) is carried out in the presence of a palladium catalyst selected from palladium(II)acetate, Pd(dppf)C1 2 , Pd(dba) 2 , tetrakis(triphenylphosphine)palladium(0) or tris(dibenzylideneacetone)dipalladium(0). In another embodiment, step a) is carried out in the presence of Pd(dba) 2 . [0033] In another embodiment, the invention features the above method wherein step a) is carried out at about 50 'C to 90 'C. In another embodiment, step a) is carried out at about 60 'C to 80 'C. In another embodiment, step a) is carried out at about 70 'C. [0034] In another embodiment, the invention features the above method wherein the second organic solvent is an aprotic solvent. In another embodiment, the second organic solvent is selected from 1,2-dimethoxyethane, dioxane, acetonitrile, toluene, benzene, xylenes, methyl t-butyl ether, methyl ethyl ketone, methyl isobutyl ketone, acetone, NN dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, ethyl acetate, dichloromethane, or dimethylsulfoxide. In another embodiment, the second organic solvent is dimethylsulfoxide. [0035] In another embodiment, the invention features the above method wherein step b) is carried out in the presence of an inorganic acid. In another embodiment, step b) is carried out in the presence of an inorganic acid selected from hydrochloric, sulfuric, nitric, phosphoric, or boric acid. In another embodiment, step b) is carried out in the presence of hydrochloric acid. -10- WO 2011/133751 PCT/US20111/033396 [00361 In another embodiment, the invention features the above method wherein step b) is carried out at about 55 'C to 95 'C. In another embodiment, step b) is carried out at about 65 'C to 85 'C. In another embodiment, step b) is carried out at about 75 'C. [0037] In another aspect, the invention features a method for preparing a compound of formula II: (Ri)m A l Hal n wherein, independently for each occurrence: ring A is a fused cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring; Hal is a halided
R
1 is independently selected from -R, -OR, -N(R) 2 , -NO 2 , halogen, -CN, -C1_ 4 haloalkyl, -C1_ 4 haloalkoxy, -C(O)N(R) 2 , -NR 2 C(O)R', -SOR', -SO 2 R,
-SO
2
N(R)
2 , -NR'SO 2 R', -COR', -CO 2 R, -NRSO 2
N(R)
2 , -COCOR; Ri is hydrogen or Ci-6 aliphatic; m is an integer from 0 to 3 inclusive; and n is an integer from 1 to 4 inclusive; comprising the steps of a) reacting a compound of formula IIA in a first organic solvent (Ri)m Hal IIA wherein, independently for each occurrence: -11- WO 2011/133751 PCT/US20111/033396 ring A is a fused cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring;
R
1 is independently selected from -R, -OR, -N(R) 2 , -NO 2 , halogen, -CN, -C1_ 4 haloalkyl, -C1_ 4 haloalkoxy, -C(O)N(R) 2 , -NR'C(O)R', -SOR', -S0 2 R,
-SO
2
N(R)
2 , -NR'SO 2 R', -CORJ, -CO 2 R, -NWSO 2
N(R)
2 , -COCOR; R is hydrogen or Ci-6 aliphatic; m is an integer from 0 to 3 inclusive; and Hal is a halide; with a compound of formula JIB: 0 x ' O RI IIB wherein X is CN or CO 2 R; R is C1_ 6 aliphatic or aryl; and W is hydrogen or C1_6 aliphatic, to form a compound of formula IIC: (Ri)m OR' x IIC wherein, independently for each occurrence: ring A is a fused cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring;
R
1 is independently selected from -Ri, -OR', -N(R) 2 , -NO 2 , halogen, -CN,
-CI
4 haloalkyl, -CI 4 haloalkoxy, -C(O)N(W) 2 , -NRC(O)R', -SOR, -SO 2 W,
-SO
2
N(RJ)
2 , -NRSO 2 R', -COR, -CO 2 R', -NR SO 2 N(Ri) 2 , -COCOR'; R is hydrogen or Ci- 6 aliphatic; -12- WO 2011/133751 PCT/US20111/033396 X is CN or CO 2 R; R is C 1
_
6 aliphatic or aryl; and m is an integer from 0 to 3 inclusive; b) removing the -CO 2 R group from compound IIC in a second organic solvent to form a compound of formula I: (Ri)m x wherein, independently for each occurrence: ring A is a fused cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring;
R
1 is independently selected from -Ri, -OR', -N(RI) 2 , -NO 2 , halogen, -CN,
-C
1
_
4 haloalkyl, -C 1
_
4 haloalkoxy, -C(O)N(R) 2 , -NR'C(O)R', -SOR', -SO 2 Rj,
-SO
2
N(RJ)
2 , -NR'SO 2 R', -CORJ, -CO 2 R', -NR'SO 2
N(RJ)
2 , -COCOR'; Ri is hydrogen or C 1 -6 aliphatic; X is CN or CO 2 R; R is C 1
_
6 aliphatic or aryl; and m is an integer from 0 to 3 inclusive; c) reacting a compound of formula I with a compound of formula IID in the presence of a base: Hal Hal q IID wherein, independently for each occurrence: Hal is a halide; and q is an integer from 0 to 3 inclusive; to produce a compound of formula IIE: -13- WO 2011/133751 PCT/US20111/033396
(R
1 )m A | x n IIE wherein, independently for each occurrence: ring A is a fused cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring; Ri is independently selected from -Ri, -OR', -N(RI) 2 , -NO 2 , halogen, -CN, -C1_ 4 haloalkyl, -C1_ 4 haloalkoxy, -C(O)N(R) 2 , -NR'C(O)R', -SOR', -SO 2 R,
-SO
2
N(RJ)
2 , -NR'SO 2 R', -CORJ, -CO2R', -NR'SO 2
N(R)
2 , -COCOR ; R is hydrogen or Ci-6 aliphatic; m is an integer from 0 to 3 inclusive; X is CN or CO 2 R; R is C 1 6 aliphatic or aryl; and n is an integer from 1 to 4 inclusive; d) sequentially reacting a compound of formula IE with a hydroxide base and acid to form a compound of formula HF: (R1)m AI OH n IIF wherein, independently for each occurrence: ring A is a fused cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring; -14- WO 2011/133751 PCT/US20111/033396
R
1 is independently selected from -Ri, -OR, -N(R) 2 , -NO 2 , halogen, -CN, -C1_ 4 haloalkyl, -C1_ 4 haloalkoxy, -C(O)N(R) 2 , -NRC(O)R', -SOR', -S0 2 R,
-SO
2
N(R)
2 , -NR'SO 2 R', -CORJ, -C0 2 R, -NRSO 2
N(R)
2 , -COCOR; Ri is hydrogen or Ci- 6 aliphatic; m is an integer from 0 to 3 inclusive; and n is an integer from 1 to 4 inclusive; and e) reacting a compound of formula IIF with a halogenating agent in a third organic solvent to form a compound of formula II. [0038] In another embodiment, the invention features the above method wherein in step a), the first organic solvent is an aprotic solvent. In another embodiment, the first organic solvent is selected from 1,2-dimethoxyethane, dioxane, acetonitrile, toluene, benzene, xylenes, methyl t-butyl ether, methyl ethyl ketone, methyl isobutyl ketone, acetone, N,N dimethylformamide, NN-dimethylacetamide, N-methylpyrrolidinone, ethyl acetate, dichloromethane, or dimethylsulfoxide. In another embodiment, the first organic solvent is toluene. [0039] In another embodiment, the invention features the above method wherein in step a), m is 0. [0040] In another embodiment, the invention features the above method wherein in step a), Hal is Br. [0041] In another embodiment, the invention features the above method wherein in step a), ring A is a fused heterocyclic or heteroaryl ring. In another embodiment, ring A is selected from 0 N _ 0 -15- WO 2011/133751 PCT/US20111/033396 F O F F ,or \ . In another embodiment, ring F><0 A is . [0042] In another embodiment, the invention features the above method wherein in step a), X is CN. In another embodiment, X is CO 2 Et. [0043] In another embodiment, the invention features the above method wherein in step a) R is Et. [0044] In another embodiment, the invention features the above method wherein in formula IIC, ring A is , m is 0, X is CN, and R' is Et. [0045] In another embodiment, the invention features the above method wherein in step b), the second solvent is an aprotic solvent. In another embodiment, the second solvent is selected from 1,2-dimethoxyethane, dioxane, acetonitrile, toluene, benzene, xylenes, methyl t butyl ether, methyl ethyl ketone, methyl isobutyl ketone, acetone, NN-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, ethyl acetate, dichloromethane, or dimethylsulfoxide. In another embodiment, the second solvent is dimethylsulfoxide. [0046] In another embodiment, the invention features the above method wherein in formula 1, ring A is rm is 0, and X is CN. [0047] In another embodiment, the invention features the above method wherein in step c), the base is an inorganic base. In another embodiment, the base is a hydroxide. In another embodiment, the base is NaOH. [0048] In another embodiment, the invention features the above method wherein in formula IID, q is 1. -16- WO 2011/133751 PCT/US2011/033396 [0049] In another embodiment, the invention features the above method wherein in formula IID, one Hal is Cl and the other Hal is Br. [00501 In another embodiment, the invention features the above method wherein in step d), the base is NaOH. In another embodiment, in step d), the acid is HCl. [0051] In another embodiment, the invention features the above method wherein in step d), reaction with a hydroxide base takes place at about 60 'C to 100 'C. In another embodiment, reaction with a hydroxide takes place at about 70 'C to 90 'C. In another embodiment, reaction with a hydroxide takes place at about 80 'C. [0052] In another embodiment, the invention features the above method wherein in formula IIE, ring A is 55, mis 0, n is 1, and X is CN. [0053] In another embodiment, the invention features the above method wherein in step e), the third organic solvent is an aprotic solvent. In another embodiment, in step e), the third organic solvent is selected from 1,2-dimethoxyethane, dioxane, acetonitrile, toluene, benzene, xylenes, methyl t-butyl ether, methyl ethyl ketone, methyl isobutyl ketone, acetone, NN dimethylformamide, NVN-dimethylacetamide, N-methylpyrrolidinone, ethyl acetate, dichloromethane, or dimethylsulfoxide. In another embodiment, in step e), the third organic solvent is toluene. [0054] In another embodiment, the invention features the above method wherein in step e), the halogenating agent is SOCl 2 . [0055] In another embodiment, the invention features the above method wherein step e) takes place at about 40 'C to 80 'C. In another embodiment, step e) takes place at about 50 'C to 70 'C. In another embodiment, step e) takes place at about 60 'C. [0056] In another embodiment, the invention features the above method wherein in formula IIF, ring A is m is 0, and n is 1. -17- WO 2011/133751 PCT/US20111/033396 [00571 In another embodiment, the invention features the above method wherein in formula II, ring A is ,m is 0, n is 1, and Hal is Cl. [0058] In another aspect, the invention features a method of preparing a compound of formula III:
H
2 N R3 ( R A O P III wherein, independently for each occurrence:
R
2 is -Ri, -OR', -N(R) 2 , -NO 2 , halogen, -CN, -C1_ 4 haloalkyl, -C1_ 4 haloalkoxy,
-C(O)N(R')
2 , -NRC(O)R, -SOR', -SO 2 R, -SO 2
N(R')
2 , -NR'SO 2 R, -COR, C0 2 R, -NRSO 2 N(Rb) 2 , -COCOR'; Ri is hydrogen or C 1
-
6 aliphatic;
R
3 is C 1
_
6 aliphatic optionally substituted with OH, OP, -O-CI-6 aliphatic, aryl, heteroaryl, -0-aryl, or -0-heteroaryl; P is a protecting group; and o is an integer from 0 to 3; comprising the steps of: a) reacting a compound of formula IIIA: 0 2 N
(R
2
)
7
NH
2 IIIA wherein, independently for each occurrence: -18- WO 2011/133751 PCT/US20111/033396
R
2 is -Ri, -OR', -N(R) 2 , -NO 2 , halogen, -CN, -C1_ 4 haloalkyl, -C1_ 4 haloalkoxy,
-C(O)N(R')
2 , -NRC(O)R, -SOR', -SO 2 R, -SO 2
N(R')
2 , -NRSO 2 R, -COR, CO 2 R, -NRSO 2
N(R')
2 , -COCOR'; Ri is hydrogen or Ci- 6 aliphatic; and o is an integer from 0 to 3; with a halogenating reagent in a first organic solvent to form a compound of formula IIIB: 0 2 N Hal
(R
2
)
7
NH
2 IIIB wherein, independently for each occurrence:
R
2 is -Ri, -OR', -N(R) 2 , -NO 2 , halogen, -CN, -C 1
_
4 haloalkyl, -C 1
_
4 haloalkoxy,
-C(O)N(RJ)
2 , -NRC(O)R, -SOR', -SO 2 R, -SO 2
N(R')
2 , -NRSO 2 R, -COR, C0 2
R
3 , -NRSO 2
N(R')
2 , -COCOR'; Ri is hydrogen or Ci- 6 aliphatic; o is an integer from 0 to 3; and Hal is a halide; b) reacting the compound of formula IIB in a second organic solvent with a compound of formula IIIC: 0 LN~O P IIIC wherein: P is a protecting group; followed by reduction and treatment with acid to form a compound of formula IIID: -19- WO 2011/133751 PCT/US20111/033396 A H 3 N Hal (R2 NH OH OP IIID wherein:
R
2 is -Ri, -OR', -N(RJ) 2 , -NO 2 , halogen, -CN, -C1_ 4 haloalkyl, -C1_ 4 haloalkoxy,
-C(O)N(RJ)
2 , -NR'C(O)Rj, -SORJ, -S0 2 RJ, -SO 2
N(RJ)
2 , -NRJSO 2 R', -COR, CO 2 R, -NRSO 2
N(R')
2 , -COCORJ; Ri is hydrogen or C 1 - aliphatic; o is an integer from 0 to 3; Hal is a halide; P is a protecting group; and A is an anion; c) neutralizing a compound of formula IIID in the presence of a base to form a compound of formula IIID-a:
H
2 N Hal
(R
2 )o NH OH OP IIID-a wherein:
R
2 is -Ri, -OR', -N(R) 2 , -NO 2 , halogen, -CN, -C1_ 4 haloalkyl, -C1_ 4 haloalkoxy,
-C(O)N(RJ)
2 , -NRC(O)R, -SORJ, -SO 2 R, -SO 2
N(RJ)
2 , -NRSO 2 R, -COR, CO 2 R, -NRSO 2
N(R')
2 , -COCORJ; -20- WO 2011/133751 PCT/US20111/033396 Ri is hydrogen or C 1 6 aliphatic; o is an integer from 0 to 3; Hal is a halide; and P is a protecting group; d) reacting a compound of formula IIID-a in a third organic solvent with a compound of formula IIIE: R3 IIIE wherein, independently for each occurrence:
R
3 is a C 1
_
6 aliphatic optionally substituted with OH, OP, -O-C 1 - aliphatic, aryl, heteroaryl, -0-aryl, or -0-heteroaryl; in the presence of a catalyst to form a compound of formula III. [00591 In another embodiment, the invention features the above method wherein in formula IIIA, o is 1. In another embodiment, o is 1 and R 2 is F. [00601 In another embodiment, the invention features the above method wherein in step a), the halogenating reagent is N-bromosuccinimide. [00611 In another embodiment, the invention features the above method wherein in step a), the first organic solvent is an aprotic solvent. In another embodiment, the first organic solvent is selected from 1,2-dimethoxyethane, dioxane, acetonitrile, toluene, benzene, xylenes, methyl t-butyl ether, methyl ethyl ketone, methyl isobutyl ketone, acetone, N,N dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, ethyl acetate, dichloromethane, or dimethylsulfoxide. In another embodiment, the first organic solvent is ethyl acetate. [00621 In another embodiment, the invention features the above method wherein step a) takes place at about 2 'C to 42 'C. In another embodiment, step a) takes place at about 12 0 C to 32 'C. In another embodiment, step a) takes place at about 22 0 C. -21- WO 2011/133751 PCT/US20111/033396 [00631 In another embodiment, the invention features the above method wherein in formula IIIB, o is 1, R 2 is F, and Hal is Br. [00641 In another embodiment, the invention features the above method wherein in formula IIIC, P is benzyl. [00651 In another embodiment, the invention features the above method wherein in step b), the second organic solvent is an aprotic solvent. In another embodiment, in step b), the second organic solvent is selected from 1,2-dimethoxyethane, dioxane, acetonitrile, toluene, benzene, xylenes, methyl t-butyl ether, methyl ethyl ketone, methyl isobutyl ketone, acetone, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, ethyl acetate, dichloromethane, or dimethylsulfoxide. In another embodiment, in step b), the second organic solvent is toluene. [00661 In another embodiment, the invention features the above method wherein in step b), the reaction with a compound of formula IIIC takes place at about 60 'C to 100 'C. In another embodiment, in step b), the reaction with a compound of formula IIIC takes place at about 70 'C to 90 'C. In another embodiment, in step b), the reaction with a compound of formula IIIC takes place at about 80 'C. [00671 In another embodiment, the invention features the above method wherein in step b), reduction is carried out with hydrogen. [00681 In another embodiment, the invention features the above method wherein in step b), the acid is p-toluenesulfonic acid. [00691 In another embodiment, the invention features the above method wherein in formula IID, o is 1, R 2 is F, Hal is Br, A- is Tos-, and P is benzyl. [00701 In another embodiment, the invention features the above method wherein in formula IIIE, R 3 is C(CH 3
)
2
CH
2 0(benzyl). [00711 In another embodiment, the invention features the above method wherein in step c), the base is an inorganic base. [0072] In another embodiment, the invention features the above method wherein in step c), the base is NaHCO 3 . -22- WO 2011/133751 PCT/US20111/033396 [00731 In another embodiment, the invention features the above method wherein in step d), the third organic solvent is an aprotic solvent. In another embodiment, in step d), the third organic solvent is selected from 1,2-dimethoxyethane, dioxane, acetonitrile, toluene, benzene, xylenes, methyl t-butyl ether, methyl ethyl ketone, methyl isobutyl ketone, acetone, NN dimethylformamide, NN-dimethylacetamide, N-methylpyrrolidinone, ethyl acetate, dichloromethane, or dimethylsulfoxide. In another embodiment, in step d), the third organic solvent is acetonitrile. [00741 In another embodiment, the invention features the above method wherein step d) takes place at about 60 'C to 100 'C. In another embodiment, step d) takes place at about 70 'C to 90 'C. In another embodiment, step d) takes place at about 80 'C. [00751 In another embodiment, the invention features the above method wherein in step d), the catalyst is a palladium catalyst. In another embodiment, in step d), the catalyst is selected from palladium(II)acetate, Pd(dppf)C1 2 , Pd(dba) 2 , (MeCN) 2 PdCl 2 , tetrakis(triphenylphosphine)palladium(0) or tris(dibenzylideneacetone)dipalladium(0). In another embodiment, in step d), the catalyst is palladium(II)acetate. [00761 In another aspect, the invention features a method of preparing a compound of formula IV: H A N R0OH (Ri)m (R2) OP IV wherein, independently for each occurrence: ring A is a fused cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring; R, and R 2 is independently selected from -RI, -OR', -N(R) 2 , -NO 2 , halogen, -CN,
-CI
4 haloalkyl, -CI 4 haloalkoxy, -C(O)N(R) 2 , -NRC(O)R', -SOR', -S0 2 R,
-SO
2
N(R')
2 , -NR'SO 2 R', -COR', -CO2R, -NR'SO 2
N(R)
2 , -COCORJ; R is hydrogen or C 1 6 aliphatic; -23- WO 2011/133751 PCT/US20111/033396
R
3 is a C1_ 6 aliphatic optionally substituted with OH, OP, -O-CI- 6 aliphatic, aryl, heteroaryl, -0-aryl, or -0-heteroaryl; P is a protecting group; m is an integer from 0 to 3 inclusive; n is an integer from I to 4 inclusive; and o is an integer from 1 to 3 inclusive; comprising the steps of: a) reacting a compound of formula IIIA: 0 2 N
(R
2 )
NH
2 IIIA wherein, independently for each occurrence:
R
2 is -Ri, -OR', -N(R) 2 , -NO 2 , halogen, -CN, -C1 4 haloalkyl, -C1_ 4 haloalkoxy,
-C(O)N(R')
2 , -NR'C(O)RI, -SOR', -SO 2 RI, -SO 2
N(R')
2 , -NR'SO 2 R', -COR', CO 2 R, -NRSO 2
N(R)
2 , -COCOR'; Ri is hydrogen or C 1 -6 aliphatic; and o is an integer from 0 to 3; with a halogenating reagent in a first organic solvent to form a compound of formula IIIB: 0 2 N Hal
(R
2 )o 7
NH
2 IIIB wherein, independently for each occurrence:
R
2 is -Ri, -OR', -N(R) 2 , -NO 2 , halogen, -CN, -C1_ 4 haloalkyl, -C1_ 4 haloalkoxy,
-C(O)N(R)
2 , -NRC(O)R, -SOR', -S0 2 R, -SO 2
N(R')
2 , -NR'SO 2 R, -COR, C0 2 R, -NRSO 2
N(R)
2 , -COCOR'; -24- WO 2011/133751 PCT/US20111/033396 Ri is hydrogen or Ci- 6 aliphatic; o is an integer from 0 to 3; and Hal is a halide; b) reacting the compound of formula IIB in a second organic solvent with a compound of formula IIIC: 0 MO P IIIC wherein: P is a protecting group; followed by reduction and treatment with acid to form a compound of formula IIID: A H 3 N Hal
(R
2 )o NH O H OP IIID wherein:
R
2 is -Ri, -OR', -N(R) 2 , -NO 2 , halogen, -CN, -CI 4 haloalkyl, -CI 4 haloalkoxy,
-C(O)N(R')
2 , -NRIC(O)R, -SOR', -SO 2 R, -SO 2
N(R')
2 , -NRSO 2 R, -COR, C0 2 R, -NRSO 2
N(R)
2 , -COCOR'; Ri is hydrogen or C, 6 aliphatic; o is an integer from 0 to 3; Hal is a halide; P is a protecting group; and E A is an anion; -25- WO 2011/133751 PCT/US20111/033396 c) neutralizing a compound of formula IIID in the presence of a base to form a compound of formula IIID-a:
H
2 N Hal (R2)o X NH OH OP IIID-a wherein:
R
2 is -Ri, -OR', -N(RI) 2 , -NO 2 , halogen, -CN, -CI 4 haloalkyl, -CI 4 haloalkoxy,
-C(O)N(R')
2 , -NRC(O)RI, -SOR', -SO 2 RI, -SO 2
N(R')
2 , -NRSO 2 R , -COR, CO 2 R', -NRSO 2
N(R')
2 , -COCOR'; R is hydrogen or C 1 6 aliphatic; o is an integer from 0 to 3; Hal is a halide; and P is a protecting group; d) reacting a compound of formula HID in a third organic solvent with a compound of formula IIIE: 0"R3 IIIE wherein, independently for each occurrence:
R
3 is a C 1
_
6 aliphatic optionally substituted with OH, OP, -O-CI- 6 aliphatic, aryl, heteroaryl, -0-aryl, or -0-heteroaryl; in the presence of a catalyst to form a compound of formula III: -26- WO 2011/133751 PCT/US20111/033396
H
2 N R3 (R2)o H ( R A O P III wherein, independently for each occurrence:
R
2 is -Ri, -OR', -N(R) 2 , -NO 2 , halogen, -CN, -C1_ 4 haloalkyl, -C1_ 4 haloalkoxy,
-C(O)N(R')
2 , -NRC(O)R, -SOR', -SO 2 R, -SO 2
N(R')
2 , -NRSO 2 R, -COR, CO 2 R, -NRSO 2
N(R')
2 , -COCOR'; Rj is hydrogen or C 1 6 aliphatic;
R
3 is C 1
_
6 aliphatic optionally substituted with OH, OP, -O-CI- 6 aliphatic, aryl, heteroaryl, -0-aryl, or -0-heteroaryl; P is a protecting group; and o is an integer from 0 to 3; e) reacting the compound of formula III in a fourth organic solvent with a compound of formula II: (Ri)m X 0 A| Hal II wherein, independently for each occurrence: ring A is a fused cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring; Hal is a halide;
R
1 is independently selected from -R, -OR', -N(R) 2 , -NO 2 , halogen, -CN, -C1_ 4 haloalkyl, -C1_ 4 haloalkoxy, -C(O)N(R) 2 , -NR'C(O)R', -SOR', -SO 2 R,
-SO
2
N(R)
2 , -NR'SO 2 RJ, -COR', -CO 2 R, -NR'SO 2
N(R)
2 , -COCOR; -27- WO 2011/133751 PCT/US20111/033396 Ri is hydrogen or C 1 6 aliphatic; m is an integer from 0 to 3 inclusive; and n is an integer from 1 to 4 inclusive; to form the compound of formula IV. [00771 In another embodiment, the invention features the above method wherein in 0F 0r'0 formula IV, ring A is selected from 1 05 o SS N S S, F F S O S or In another embodiment, in formula IV, ring A is S [00781 In another embodiment, the invention features the above method wherein in formula IV, m is 0. In another embodiment, in formula IV, n is 1. In another embodiment, in formula IV, o is 1 and R 2 is F. [00791 In another embodiment, the invention features the above method wherein in formula IV, P is benzyl. [00801 In another embodiment, the invention features the above method wherein in formula IV, R 3 is a C 4 aliphatic optionally substituted with OP. In another embodiment, in formula IV, R 3 is OP. In another embodiment, in formula IV, R 3 is -28- WO 2011/133751 PCT/US20111/033396 [00811 In another embodiment, the invention features the above method wherein in formula IV, ring A is ,m is 0, n is 1, o is 1 and R 2 is F, P is benzyl, and R 3 is [00821 In another embodiment, the invention features the above method wherein in step a), the halogenating reagent is N-bromosuccinimide. [00831 In another embodiment, the invention features the above method wherein in step a), the first organic solvent is an aprotic solvent. In another embodiment, in step a), the first organic solvent is selected from 1,2-dimethoxyethane, dioxane, acetonitrile, toluene, benzene, xylenes, methyl t-butyl ether, methyl ethyl ketone, methyl isobutyl ketone, acetone, NN dimethylformamide, NN-dimethylacetamide, N-methylpyrrolidinone, ethyl acetate, dichloromethane, or dimethylsulfoxide. In another embodiment, in step a), the first organic solvent is ethyl acetate. [00841 In another embodiment, the invention features the above method wherein step a) takes place at about 2 'C to 42 'C. In another embodiment, step a) takes place at about 12 'C to 32 'C. In another embodiment, step a) takes place at about 22 'C. [00851 In another embodiment, the invention features the above method wherein in formula IIIB, o is 1, R 2 is F, and Hal is Br. [00861 In another embodiment, the invention features the above method wherein in formula IIIC, P is benzyl. [00871 In another embodiment, the invention features the above method wherein in step b), the second organic solvent is an aprotic solvent. In another embodiment, in step b), the second organic solvent is selected from 1,2-dimethoxyethane, dioxane, acetonitrile, toluene, benzene, xylenes, methyl t-butyl ether, methyl ethyl ketone, methyl isobutyl ketone, acetone, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, ethyl acetate, -29- WO 2011/133751 PCT/US20111/033396 dichloromethane, or dimethylsulfoxide. In another embodiment, in step b), the second organic solvent is toluene. [00881 In another embodiment, the invention features the above method wherein in step b), the reaction with a compound of formula IIIC takes place at about 60 'C to 100 'C. In another embodiment, in step b), the reaction with a compound of formula lIC takes place at about 70 'C to 90 'C. In another embodiment, in step b), the reaction with a compound of formula IIIC takes place at about 80 'C. [00891 In another embodiment, the invention features the above method wherein in step b), reduction is carried out with hydrogen. [00901 In another embodiment, the invention features the above method wherein in step b), the acid is p-toluenesulfonic acid. [00911 In another embodiment, the invention features the above method wherein in formula IID, o is 1, R 2 is F, Hal is Br, A- is Tos-, and P is benzyl. [00921 In another embodiment, the invention features the above method wherein in formula IIIE, R 3 is C(CH 3
)
2
CH
2 0(benzyl). [00931 In another embodiment, the invention features the above method wherein in step c), the base is an inorganic base. [00941 In another embodiment, the invention features the above method wherein in step c), the base is NaHCO 3 . [00951 In another embodiment, the invention features the above method wherein in step d), the third organic solvent is an aprotic solvent. In another embodiment, in step d), the third organic solvent is selected from 1,2-dimethoxyethane, dioxane, acetonitrile, toluene, benzene, xylenes, methyl t-butyl ether, methyl ethyl ketone, methyl isobutyl ketone, acetone, NN dimethylformamide, NN-dimethylacetamide, N-methylpyrrolidinone, ethyl acetate, dichloromethane, or dimethylsulfoxide. In another embodiment, in step d), the third organic solvent is acetonitrile. -30- WO 2011/133751 PCT/US20111/033396 [00961 In another embodiment, the invention features the above method wherein step d) takes place at about 60 'C to 100 'C. In another embodiment, step d) takes place at about 70 'C to 90 'C. In another embodiment, step d) takes place at about 80 'C. [0097] In another embodiment, the invention features the above method wherein in step d), the catalyst is a palladium catalyst. In another embodiment, in step d), the catalyst is selected from palladium(II)acetate, Pd(dppf)Cl 2 , Pd(dba) 2 , tetrakis(triphenylphosphine)palladium(0) or tris(dibenzylideneacetone)dipalladium(O). In another embodiment, in step d), the catalyst is palladium(II)acetate. [00981 In another embodiment, the invention features the above method wherein in step e), ring A is ,m is 0, n is 1, and Hal is Cl. [00991 In another embodiment, the invention features the above method wherein in step e), the fourth organic solvent is an aprotic solvent. In another embodiment, in step e), the fourth organic solvent is selected from 1,2-dimethoxyethane, dioxane, acetonitrile, toluene, benzene, xylenes, methyl t-butyl ether, methyl ethyl ketone, methyl isobutyl ketone, acetone, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, ethyl acetate, dichloromethane, or dimethylsulfoxide. In another embodiment, in step e), the fourth organic solvent is dichloromethane. [00100] In another embodiment, the invention features the above method wherein step e) takes place at about -20 'C to 20 'C. In another embodiment, step e) takes place at about -10 'C to 10 'C. In another embodiment, step e) takes place at about 0 'C. [00101] In another embodiment, the invention features the above method wherein in step e), the compound of formula II is prepared in situ by halogenating the acid precursor and reacted with the compound of formula III without isolation. [001021 In another embodiment, the invention features the above method further comprising removing the two protecting groups from the compound of formula IV to form a compound of formula IVA: -31- WO 2011/133751 PCT/US20111/033396 H Al NOH (Ri)m (R 2 )o OH IVA. [00103] In another embodiment, the protecting groups are removed by hydrogenation. [00104] In another aspect, the invention features a method of preparing Compound 1: H ON F
-
N
F
0 l 0 EN OH FNHOH 3 comprising the steps of: a) reacting compound 2: 0 2 N F) NH 2 2 with a brominating reagent to form a compound 3: 0 2 N F (:NH 2 3 b) reacting compound 3 with compound 4: O Bn 4 followed by reduction to formn compound 5: -32- WO 2011/133751 PCT/US20111/033396 TsO H 3 N Br F CNH OH OBn 5 followed by neutralizing compound 5 with a base to give compound 5a:
H
2 N Hal (R)o NH OH OBn 5a c) reacting compound 5awith compound 6: OBn 6 in the presence of a catalyst to form compound 7:
H
2 N OBn OBn 7 d) reacting compound 7 with compound 8: O CI F o 8 to form compound 9: -33- WO 2011/133751 PCT/US20111/033396 H F NNOBn F :0 0F !0N OH OBn 9 and e) removing the two Bn protecting groups to form Compound 1. [00105] In another embodiment, the invention features the above method wherein in step a), the brominating agent is N-bromosuccinimide. [00106] In another embodiment, the invention features the above method wherein in setp b), the reduction is carried out with hydrogen. [00107] In another embodiment, the invention features the above method wherein in setp b), the base is an inorganic base. [00108] In another embodiment, the invention features the above method wherein in setp b), the base is NaHCO 3 . [00109] In another embodiment, the invention features the above method wherein in step c), the catalyst is a palladium catalyst. In another embodiment, in step c), the catalyst is selected from palladium(II)acetate, Pd(dppf)C1 2 , Pd(dba) 2 , tetrakis(triphenylphosphine)palladium(O) or tris(dibenzylideneacetone)dipalladium(O). In another embodiment, in step c), the catalyst is palladium(II)acetate. [001101 In another embodiment, the invention features the above method wherein in step d), compound 8 is made in situ by halogenating the acid precursor without isolation. [00111] In another embodiment, the invention features the above method wherein in step e), the Bn protecting groups are removed by hydrogenation. [00112] In another aspect, the invention features a compound of formula 23: -34- WO 2011/133751 PCT/US20111/033396 (R1)m A 0 OR' x 23 wherein: ring A is a fused cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring; Ri is independently selected from -Ri, -OR', -N(R) 2 , -NO 2 , halogen, -CN,
-C
1
_
4 haloalkyl, -C1_ 4 haloalkoxy, -C(O)N(Rj) 2 , -NR'C(O)R', -SOR', -SO 2 Rj,
-SO
2
N(R)
2 , -NR'SO 2 R', -COR', -CO 2 R, -NRSO 2
N(R)
2 , -COCOR; Ri is hydrogen or C 1 6 aliphatic; X is CN or CO 2 R; R is C 1
_
6 aliphatic or aryl; and m is an integer from 0 to 3 inclusive. [00113] In another embodiment, the invention features a compound of formula 23 and the attendant definitions, wherein ring A is a fused heterocycloalkyl or heteroaryl. In another < oX embodiment, ring A is selected from 5 0 0 5 3 NS~, ~ F S S O Sor F 0 . In another embodiment, ring A is . [00114] In another embodiment, the invention features a compound of formula 23 and the attendant definitions, wherein X is CN. In another embodiment, X is CO 2 Et. -35- WO 2011/133751 PCT/US20111/033396 [00115] In another embodiment, the invention features a compound of formula 23 and the attendant definitions, wherein m is 0. [00116] In another embodiment, the invention features a compound of formula 23 and the attendant definitions, wherein R is C 1
_
6 aliphatic. In another embodiment, Rj is -CH 2
CH
3 . [00117] In another aspect, the invention features the compound FXO i 0 F OD:; 0 F 0 OEt CN [001] In another aspect, the invention features the compound F 0 N 0 F 0 OEt [001181 0 OEt [00119] Methods ofPreparing Compounds of Formulas I, III, and IV [00120] Compounds of formulas I, II, II, and IV may be prepared by the methods of Schemes 1-3. -36- WO 2011/133751 PCT/US20111/033396 [00121] Scheme 1. Compounds of formula I and II. (Rj)m A R~ 0 a Al0 I Hal OR a OR' X IA IB IC (Ri)m A 0 d,eR)m Hal Hal OH - Al q (R1)m n CD IIF IIE If (Rl)m Al Hal n II [00122] a = Pd(O) catalyst; b = acid; c = base; d = hydroxide base; e = acid; f= halogenating agent; [00123] wherein ring A, R 1 , m, X, R, Hal, q, and n are as defined above. [00124] In Scheme 1, aryl halide IA is reacted with ester IB in the presence of a transition metal catalyst in a suitable solvent (e.g. toluene) to produce ester IC. In esters IB and IC, X can either be CN or CO 2 R. Treatment of IC with an acid in a suitable solvent (e.g. dimethyl sulfoxide (DMSO)) produces I. Reaction of I with the dihalide IID in the presence of base gives the cycloalkylidene IIE. Hydrolization of the cyanide or remaining ester group -37- WO 2011/133751 PCT/US2011/033396 depending on the identity of X gives the carboxylic acid IIF which is halogenated to yield the acid halide II. [00125] In one embodiment, IA is commercially available. In one embodiment, ring A is a 5 membered dioxyl ring. In one embodiment, Hal in IA is Br. In one embodiment, the reaction of IA and 1IB takes place in toluene in the presence of a Pd(0) caystalyst, e.g. Pd(dba) 2 . In a further embodiment, the reaction takes place in the presence of an alkyl phosphine, e.g. t Bu3P and phosphate salt, e.g. Na 3
PO
4 . In another embodiment, the reaction of IA and TIB takes place at about 70 'C. In another embodiment, R' is Et. [00126] In one embodiment, the de-esterification of IC to I is done with an inorganic acid. In a further embodiment, the inorganic acid is HCl. The conversion takes place in an appropriate aprotic solvent (e.g. DMSO) at about 75 'C. [00127] In one embodiment, I is reacted with NaOH and an alkyl dihalide to yield the cycloalkylidene in a suitable solvent (e.g. MTBE). The process is adaptable to several spirocyclic rings by choosing the appropriate alkyl dihalide. For example, a spirocylic butane ring can be produced by reacting I with, for example, 1-bromo-3-chloropropane. It has been found that a mixed bromo and chloro dihalide works best on an economic scale as it is believed that the thermodynamics of the reaction are more favorable. [00128] In one embodiment, HE is hydrolized to the carboxylic acid IIF in the presence of water and a base (e.g. NaOH) in a suitable solvent (e.g. ethanol). Subseqent treatment with an acid such as HCl yields HF. In another embodiment, IIF is worked up by recrystallizing it from toluene. [00129] In one embodiment, the halogenating agent that converts IIF to II is thionyl chloride. In another embodiment, the thionyl chloride is added to IIF in toluene at about 60 'C. In one embodiment, this step directly proceeds the coupling between II and amine III (see below) and is carried out in the same reaction vessel. [00130] There are several non-limiting advantages to forming II according to Scheme 1 and the embodiments described above and elsewhere in the application. These advantages are apparent even more so when manufacturing II on an economic scale and include the following. The overall reaction requires only 5 steps, which is less than what's been previously reported -38- WO 2011/133751 PCT/US20111/033396 (i.e. starting from an aryl carboxylic acid, which is reduced to the methyl alcohol, which is converted to a methyl chloride, which is reacted with NaCN). This synthetic route introduces the CN or ester group (i.e. X) without a separate chlorinating reaction. Using ethanol as the cosolvent in hydrolyzing IE to IIF results in a homogeneous reaction mixture making sampling and monitoring the reaction easier. Recrystallizing IIF from toluene eliminates the need for forming a dicyclohexylamine (DCA) salt as previously reported. [00131] Scheme 2. Compounds of formula III. 02N 0 2 N Hal (R2)2 (R2)0 NH 2 IIIA IIB 0 ' OP b, c, d IIIC
R
3 H2T3H IIE H 2 N HlAH3N..yHal (R2)O f (R2)o NH e (R2)o NH OOP OH Ill IIID-a OP IIID P [00132] a = halogenating agent; b = Zn(II) catalyst; c = H 2 , Pt; d = acid; e = base; f= Pd(II) catalyst; 0 [00133] wherein R 2 , o, Hal, A , and P are defined as above. [00134] In one embodiment, in IIIA, R 2 is F and is meta to the amine group. In another embodiment, IIIA is brominated with N-bromosuccinimide in a suitable solvent (e.g. ethylacetate) at about 22 'C. -39- WO 2011/133751 PCT/US20111/033396 [00135] In another embodiment, IIIB is reacted with epoxide IIIC effecting a ring opening reaction with the amine group of IIIB to form IIID. In one embodiment, the protecting group, P, in IIIC is benzyl (Bn). In another embodiment epoxide IIIC is chiral. In one embodiment IIIC is (R) IIIC. In another embodiment, IIIC is (S) IIIC. In one embodiment, the ring opening reaction is carried out in a suitable solvent (e.g. toluene) at about 80 'C. In another embodiment, the ring opening reaction takes place in the presence of a Zn(II) catalyst (e.g. Zn(Cl0 4
)
2 ). In another embodiment, the conversion from IIIB to IIID comprises the ring opening reaction with epoxide IIIC, followed by hydrogenation, and then treatment with an acid to form IIID. In a further embodiment, hydrogenation is carried out with H 2 /Pt(S)/C. In a a further embodiment, the acid is toluene sulfonic acid, such that A is a tosylate anion. [001361 In another embodiment, alkyne IIIE is coupled with HID in a suitable solvent (e.g. acetonitrile) at about 80 'C. In another embodiment, the coupling reaction takes place in the presence of a Pd(II) catalyst, such as Pd(OAc) 2 . The initial reaction does not result in ring closure, only replacement of the halide on IIID. Ring closure is accomplished through reaction with another Pd(II) catalyst, such as (McCN) 2 PdCI 2 in a suitable solvent (e.g. acetonitrile). In one embodiment, ring closure takes place at about 80 'C. In one embodiment, R, in alkyne IIIE is -C(CH3;) 2
CH
2 OBn. In one embodiment, the product from the coupling reaction is not isolated but taken up in acetonitrile and reacted with (MeCN) 2 PdCl 2 . [00137] There are several non-limiting advantages to forming compound III according to Scheme 2 and the embodiments described above and elsewhere in the application. These advantages are apparent even more so when manufacturing III on an economic scale and include the following. The overall number of steps have been reduced compared to what was disclosed previously to just 3 steps. Other advantages include the elimination of chromatography and by-products from protecting groups. -40- WO 2011/133751 PCT/US2011/033396 [00138] Scheme 3. Compounds of Formula IV. (Ri)m (R )m Al 0 a X OHA O H / Hal n IIF II b H 2 N R3 (R2) 0 III n( H N AlR HOH (Ri)m (R2) 0 IV [00139] a = halogenating agent; b = aprotic solvent; [00140] wherein ring A, R 1 , m, n, hal, R2, o, P, and R3 are as defined above. [00141] An acid-base reaction between II and III in a suitable solvent (e.g. dichloromethane (DCM)) yields the protected analog of Compound 1. In one embodiment, the acid halide II is prepared from IIF as depicted in Scheme 1 in the same reaction vessel and is not isolated. In another embodiment, the acid-based reaction is carried out in the presence of a base such as triethylamine (TEA). In one embodiment, the amount of TEA is 2 equivalents relative to II. In one embodiment, after a reaction time of about 4 hours at about 0 'C and warming to room temperature overnight, water is added to the mixture and stirred for an additional 30 minutes. The organic phase is separated and IV is isolated by distilling off the reaction solvent. In one embodiment, IV is collected by silica pad filtration. -41- WO 2011/133751 PCT/US20111/033396 [00142] In another embodiment, compounds of formula IV may be deprotected to form compounds of formula IVa according to Scheme 4. [00143] Scheme 4. Deprotecting Compounds of Formula IV. H NH a N 3 A |0 O N 30H a o R3 NR~ OH 2 ) 0 ! OH (R ) m (R 2 P (Ri)m
(R
2
)
0 IV IVa [00144] a = H 2 /Pd/C; [00145] wherein ring A, R 1 , m, n, R 2 , o, R 3 , and P are defined as above. [00146] In one embodiment, hydrogen pressurization is 3 Bars. In another embodiment, the hydrogenation agitation rate is increased to 800 rpm. In another embodiment, after rapid hydrogen uptake subsides, the hydrogenation vessel is heated to about 50 'C for 2 days. In another embodiment, after the 2 days, more catalyst is added and hydrogenation continues for another 4 days. In another embodiment, IV is dissolved in a suitable solvent (e.g. THF). [00147] In another embodiment, Compound 1 may be prepared by coupling the acid halide moiety 7 with the amine moiety 8 to form compound 9 followed by deprotection according to Scheme 5. -42- WO 2011/133751 PCT/US20111/033396 [00148] Scheme 5. Preparation of Compound 1.
H
2 N OBn F F CI O OBn >0 - CI F>0 F F 7 F OH 7OH Et 3 N, DCM, toluene
H
2 , Pd / C HCl-MeOH H FF N N O OH Compound 1 OH [00149] Wherein Compound 7 is prepared according to Scheme 6. -43- WO 2011/133751 PCT/US20111/033396 [00150] Scheme 6. F + 0 Pd(dba) 2 , t-BuFP O FoJ CN ~POF O F 0 Br EtO Na 3
PO
4 , F 0 OEt Touene, H20, 70 0 C CN 3 N HCl, DMSO, i 75 0 C FOI ON Br2 C F 0 ;; N F CN NaOH F O CN Bu 4 NBr 1. NaOH 2. HCl
F
0 O SOC 2
F
0 C1 FO0 OH FO0c 7 [00151] Wherein Compound 8 is prepared according to Scheme 7. -44- WO 2011/133751 PCT/US20111/033396 [00152] Scheme 7. TMS OH conc HCI 1. Mg, THF OBn KOH OBn TMVS RT TMVS eX 2. BO MCI TMVS MO 0 2 N NBS NB N Br 1) Z( 20 HNr base - .Zn(C0O 4
)
2 2 2 0 F NH bs F NH 2 EtOAc F NH 2 2) H 2 , Pt(S)/C TsO 0 OH 3) TsOH-H 2 0 OBn OBnHN OBn
H
2 N (CP H2N OBn (MeCN) 2 PdC 2 F N Pd(OAc), dppb, F NH Cul OH
K
2
CO
3 , Cul, water OH 8 OBn [00153 Uses. Formulation and Administration [001541 Pharmaceutically acceptable compositions [00155] In another aspect of the present invention, pharmaceutically acceptable compositions are provided, wherein these compositions comprise Compound 1 Form A or amorphous Compound 1 as described herein, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents. [001561 As described above, the pharmaceutically acceptable compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a -45- WO 2011/133751 PCT/US20111/033396 deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. [00157] Uses of Compounds and Pharmaceutically Acceptable Compositions [00158] In yet another aspect, the present invention provides a method of treating a condition, disease, or disorder implicated by CFTR. In certain embodiments, the present invention provides a method of treating a condition, disease, or disorder implicated by a deficiency of CFTR activity, the method comprising administering a composition comprising a Compound 1 described herein to a subject, preferably a mammal, in need thereof. [00159] A "CFTR-mediated disease" as used herein is a disease selected from cystic fibrosis, asthma, smoke induced COPD, chronic bronchitis, rhinosinusitis, constipation, pancreatitis, pancreatic insufficiency, male infertility caused by congenital bilateral absence of the vas deferens (CBAVD), mild pulmonary disease, idiopathic pancreatitis, allergic -46- WO 2011/133751 PCT/US20111/033396 bronchopulmonary aspergillosis (ABPA), liver disease, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, such as protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as I-cell disease/pseudo-Hurler, mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type II, polyendocrinopathy/hyperinsulemia, Diabetes mellitus, Laron dwarfism, myleoperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI), neurophyseal DI, neprogenic DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear plasy, Pick's disease, several polyglutamine neurological disorders such as Huntington's, spinocerebullar ataxia type I, spinal and bulbar muscular atrophy, dentatorubal pallidoluysian, and myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary Creutzfeldt-Jakob disease (due to prion protein processing defect), Fabry disease, Straussler-Scheinker syndrome, COPD, dry-eye disease, or Sjogren's disease, Osteoporosis, Osteopenia, bone healing and bone growth (including bone repair, bone regeneration, reducing bone resorption and increasing bone deposition), Gorham's Syndrome, chloride channelopathies such as myotonia congenita (Thomson and Becker forms), Bartter's syndrome type III, Dent's disease, hyperekplexia, epilepsy, hyperekplexia, lysosomal storage disease, Angelman syndrome, and Primary Ciliary Dyskinesia (PCD), a term for inherited disorders of the structure and/or function of cilia, including PCD with situs inversus (also known as Kartagener syndrome), PCD without situs inversus and ciliary aplasia. In another embodiment, the CFTR mediated disease is cystic fibrosis, emphysema, COPD, or osteoporosis. In another embodiment, the CFTR mediated disease is cystic fibrosis. [00160] In certain embodiments, the present invention provides a method of treating a CFTR-mediated disease in a human comprising the step of administering to said human an effective amount of a composition comprising Compound 1 described herein. -47- WO 2011/133751 PCT/US20111/033396 [00161] According to the invention an "effective amount" of Compound 1 Form A or amorphous Compound 1 or a pharmaceutically acceptable composition thereof is that amount effective for treating or lessening the severity of any of the diseases recited above. [00162] Compound 1 or a pharmaceutically acceptable composition thereof may be administered using any amount and any route of administration effective for treating or lessening the severity of one or more of the diseases recited above. [001631 In certain embodiments, Compound 1 described herein or a pharmaceutically acceptable composition thereof is useful for treating or lessening the severity of cystic fibrosis in patients who exhibit residual CFTR activity in the apical membrane of respiratory and non-respiratory epithelia. The presence of residual CFTR activity at the epithelial surface can be readily detected using methods known in the art, e.g., standard electrophysiological, biochemical, or histochemical techniques. Such methods identify CFTR activity using in vivo or ex vivo electrophysiological techniques, measurement of sweat or salivary Cl- concentrations, or ex vivo biochemical or histochemical techniques to monitor cell surface density. Using such methods, residual CFTR activity can be readily detected in patients heterozygous or homozygous for a variety of different mutations, including patients homozygous or heterozygous for the most common mutation, AF508. [00164] In one embodiment, Compound 1 described herein or a pharmaceutically acceptable composition thereof is useful for treating or lessening the severity of cystic fibrosis in patients within certain genotypes exhibiting residual CFTR activity, e.g., class III mutations (impaired regulation or gating), class IV mutations (altered conductance), or class V mutations (reduced synthesis) (Lee R. Choo-Kang, Pamela L., Zeitlin, Type I, II, III, IV, and V cystic fibrosis Tansmnembrane Conductance Regulator Defects and Opportunities of Therapy; Current Opinion in Pulmonary Medicine 6:521 - 529, 2000). Other patient genotypes that exhibit residual CFTR activity include patients homozygous for one of these classes or heterozygous with any other class of mutations, including class I mutations, class II mutations, or a mutation that lacks classification. [00165] In one embodiment, Compound 1 described herein or a pharmaceutically acceptable composition thereof is useful for treating or lessening the severity of cystic fibrosis -48- WO 2011/133751 PCT/US20111/033396 in patients within certain clinical phenotypes, e.g., a moderate to mild clinical phenotype that typically correlates with the amount of residual CFTR activity in the apical membrane of epithelia. Such phenotypes include patients exhibiting pancreatic insufficiency or patients diagnosed with idiopathic pancreatitis and congenital bilateral absence of the vas deferens, or mild lung disease. [00166] The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. The compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression "dosage unit form" as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts. The term "patient" or "subject", as used herein, means an animal, preferably a mammal, and most preferably a human. [001671 The pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated. In certain embodiments, the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect. -49- WO 2011/133751 PCT/US20111/033396 [00168] In certain embodiments, the dosage amount of Compound 1 in the dosage unit form is from 100 mg to 1,000 mg. In another embodiment, the dosage amount of Compound 1 is from 200 mg to 900 mg. In another embodiment, the dosage amount of Compound 1 is from 300 mg to 800 mg. In another embodiment, the dosage amount of Compound 1 is from 400 mg to 700 mg. In another embodiment, the dosage amount of Compound 1 is from 500 mg to 600 mg. [00169] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. [00170] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. [00171] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound. [00172] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating -50- WO 2011/133751 PCT/US20111/033396 agents such as agar--agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as tale, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. [00173] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like. [00174] The active compounds can also be in microencapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. -51- WO 2011/133751 PCT/US20111/033396 Examples of embedding compositions that can be used include polymeric substances and waxes. [001751 It will also be appreciated that Compound 1 described herein or a pharmaceutically acceptable composition thereof can be employed in combination therapies, that is, Compound 1 can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another agent used to treat the same disorder), or they may achieve different effects (e.g., control of any adverse effects). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated". [00176] In one embodiment, the additional agent is selected from a mucolytic agent, bronchodialator, an anti-biotic, an anti-infective agent, an anti-inflammatory agent, a CFTR modulator other than a compound of the present invention, or a nutritional agent. [001771 In one embodiment, the additional therapeutic agent is an antibiotic. Exemplary antibiotics useful herein include tobramycin, including tobramycin inhaled powder (TIP), azithromycin, aztreonam, including the aerosolized form of aztreonam, amikacin, including liposomal formulations thereof, ciprofloxacin, including formulations thereof suitable for administration by inhalation, levoflaxacin, including aerosolized formulations thereof, and combinations of two antibiotics, e.g., fosfomycin and tobramycin. [00178] In another embodiment, the additional agent is a mucolyte. Exemplary mucolytes useful herein includes Pulmozyme@. [00179] In another embodiment, the additional agent is a bronchodialator. Exemplary bronchodialtors include albuterol, metaprotenerol sulfate, pirbuterol acetate, salmeterol, or tetrabuline sulfate. -52- WO 2011/133751 PCT/US20111/033396 [00180] In another embodiment, the additional agent is effective in restoring lung airway surface liquid. Such agents improve the movement of salt in and out of cells, allowing mucus in the lung airway to be more hydrated and, therefore, cleared more easily. Exemplary such agents include hypertonic saline, denufosol tetrasodium ([[(3S, 5R)-5-(4-amino-2 oxopyrimidin-1-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4R,5R)-5 (2,4-dioxopyrimidin-1-yl)-3, 4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy hydroxyphosphoryl] hydrogen phosphate), or bronchitol (inhaled formulation of mannitol). [00181] In another embodiment, the additional agent is an anti-inflammatory agent, i.e., an agent that can reduce the inflammation in the lungs. Exemplary such agents useful herein include ibuprofen, docosahexanoic acid (DHA), sildenafil, inhaled glutathione, pioglitazone, hydroxychloroquine, or simavastatin. [001821 In another embodiment, the additional agent is a CFTR modulator other than Compound 1, i.e., an agent that has the effect of modulating CFTR activity. Exemplary such agents include ataluren ("PTC 124®"; 3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid), sinapultide, lancovutide, depelestat (a human recombinant neutrophil elastase inhibitor), cobiprostone (7- {(2R, 4aR, 5R, 7aR)-2-[(3S)- 1,1 -difluoro-3-methylpentyl]-2-hydroxy-6 oxooctahydrocyclopenta[b]pyran-5-yl}heptanoic acid), and N-(5-hydroxy-2,4-ditert-butyl phenyl)-4-oxo-1H-quinoline-3-carboxamide. [00183] In another embodiment, the additional agent is a nutritional agent. Exemplary nutritional agents include pancrelipase (pancreating enzyme replacement), including Pancreases, Pancreacarb@, Ultrase®, or Creon@, Liprotomase® (formerly Trizytek®), Aquadeks®, or glutathione inhalation. In one embodiment, the additional nutritional agent is pancrelipase. [00184] In another embodiment, the additional agent is a compound selected from gentamicin, curcumin, cyclophosphamide, 4-phenylbutyrate, miglustat, felodipine, nimodipine, Philoxin B, geniestein, Apigenin, cAMP/cGMP modulators such as rolipram, sildenafil, milrinone, tadalafil, amrinone, isoproterenol, albuterol, and almeterol, deoxyspergualin, HSP 90 inhibitors, HSP 70 inhibitors, proteosome inhibitors such as epoxomicin, lactacystin, etc. -53- WO 2011/133751 PCT/US20111/033396 [001851 In another embodiment, th: additional agent is a compound disclosed in WO 2004028480, WO 2004110352, VO 20050S4374, WO 2005120497, or WO 2006101740. [001861 In another embodiment, the additional agent is a benzo(c)quinolizinium derivative that exhibits CFTR modulation activity or a benzopyran derivative that exhibits CFTR modulation activity. [001871 In another embodiment, the addditional agent is a compound disclosed in US7202262, US6992096, US2006014886 4, US2 )060148863, US20060035943, US20050164973, W02006110483, W021,06044456, W02006044682, W02006044505, W02006044503, W02006044502, or WO 200409 1502. [00188] In another embodiment, the additional agent is a compound disclosed in W02004080972, W02004111014, WO20050355 14, W02005049018, W02006099256, W02006127588, or W02007044560. [001891 These combinations are useful for treating the diseases described herein including cystic fibrosis. These combinations are also useful in the kits described herein. 1001901 The amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably the amount of additional therapeutic agent in the presently dis;closed compositions will range from about 50% to 100% of the amount normally present in a. composition comprising that agent as the only therapeutically active agent. 1001911 In order that the invention described herein may be more fully understood, the following examples are set forth, It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner. EXAMPLES [00192] Methods & Materials [001931 Vitride@ (sodium bis(2-methcxyethoxy)aluminum hydride [or NaAIH 2
(OCH
2 CH20CH 3
)
2 ], 65 wgt/o solution in toluene) was purchased from Aldrich Chemicals. 3-Fluoro-4-nitroaniline was purchased from Capot Chemicals. 5-Bromo-2,2 54 WO 2011/133751 PCT/US20111/033396 difluoro-1,3-benzodioxole was purchased from Alfa Aesar. 2,2-Difluoro-1,3-benzodioxole-5 carboxylic acid was purchased from Saltigo (an affiliate of the Lanxess Corporation). [00194] Anywhere in the present application where a name of a compound may not correctly describe the structure of the compound, the structure supersedes the name and governs. [001951 Synthesis of Compound 1 [00196] Acid Moiety [001971 Synthesis of (2,2-difluoro-1,3-benzodioxol-5-yl)-1-ethylacetate-acetonitrile ±:1a- Pd(dba) 2 , t-Bu 3 P F, F O Br EtO N a tB, F 0 O Et Touene, H2, 70 OC CN [00198] A reactor was purged with nitrogen and charged with 900 mL of toluene. The solvent was degassed via nitrogen sparge for no less than 16 h. To the reactor was then charged Na 3
PO
4 (155.7 g, 949.5 mmol), followed by bis(dibenzylideneacetone) palladium (0) (7.28 g, 12.66 mmol). A 10% w/w solution of tert-butyiphosphine in hexanes (51.23 g, 25.32 mmol) was charged over 10 min at 23 'C from a nitrogen purged addition funnel. The mixture was allowed to stir for 50 min, at which time 5-bromo-2,2-difluoro-1,3-benzodioxole (75 g, 316.5 mmol) was added over 1 min. After stirring for an additional 50 min, the mixture was charged with ethyl cyanoacetate (71.6 g, 633.0 mmol) over 5 min followed by water (4.5 mL) in one portion. The mixture was heated to 70 'C over 40 min and analyzed by HPLC every 1 - 2 h for the percent conversion of the reactant to the product. After complete conversion was observed (typically 100% conversion after 5 - 8 h), the mixture was cooled to 20 - 25 'C and filtered through a celite pad. The celite pad was rinsed with toluene (2 X 450 mL) and the combined organics were concentrated to 300 mL under vacuum at 60 - 65 'C. The concentrate was charged with 225mL DMSO and concentrated under vacuum at 70 - 80 'C until active distillation of the solvent ceased. The solution was cooled to 20 - 25 'C and diluted to 900 mL with DMSO in preparation for Step 2. 'H NMR (500 MHz, CDCl 3 ) 6 7.16 - 7.10 (m, 2H), 7.03 (d, J= 8.2 Hz, 1H), 4.63 (s, 1H), 4.19 (in, 2H), 1.23 (t, J= 7.1 Hz, 3H). -55- WO 2011/133751 PCT/US20111/033396 [00199] Synthesis of (2,2-difluoro-1,3-benzodioxol-5-yl)-acetonitrile. F O 3N H Cl, F 0CN F 0 OEt DMSO, 75 0 C F O CN [00200] The DMSO solution of (2,2-difluoro-1,3-benzodioxol-5-yl)-l-ethylacetate acetonitrile from above was charged with 3 N HCI (617.3 mL, 1.85 mol) over 20 min while maintaining an internal temperature < 40 'C. The mixture was then heated to 75'C over 1 h and analyzed by HPLC every 1 - 2 h for % conversion. When a conversion of > 99% was observed (typically after 5 - 6 h), the reaction was cooled to 20 - 25 'C and extracted with MTBE (2 X 525 mL), with sufficient time to allow for complete phase separation during the extractions. The combined organic extracts were washed with 5% NaCl (2 X 375 mL). The solution was then transferred to equipment appropriate for a 1.5 - 2.5 Torr vacuum distillation that was equipped with a cooled receiver flask. The solution was concentrated under vacuum at < 60'C to remove the solvents. (2,2-Difluoro-1,3-benzodioxol-5-yl)-acetonitrile was then distilled from the resulting oil at 125 - 130 'C (oven temperature) and 1.5 - 2.0 Torr. (2,2 Difluoro-1,3-benzodioxol-5-yl)-acetonitrile was isolated as a clear oil in 66% yield from 5 bromo-2,2-difluoro-1,3-benzodioxole (2 steps) and with an HPLC purity of 91.5% AUC (corresponds to a w/w assay of 95%). 1 H NMR (500 MHz, DMSO) 6 7.44 (br s, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.22 (dd, J= 8.2, 1.8 Hz, 1H), 4.07 (s, 2H). [00201] Synthesis of (2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonitrile. FCN C B r -CN Bu 4 NBr, 50% w/w NaOH MTBE [00202] A stock solution of 50% w/w NaOH was degassed via nitrogen sparge for no less than 16 h. An appropriate amount of MTBE was similarly degassed for several hours. To a reactor purged with nitrogen was charged degassed MTBE (143 mL) followed by (2,2 difluoro-1,3-benzodioxol-5-yl)-acetonitrile (40.95 g, 207.7 mmol) and tetrabutylammonium bromide (2.25 g, 10.38 mmol). The volume of the mixture was noted and the mixture was degassed via nitrogen sparge for 30 min. Enough degassed MTBE is charged to return the -56- WO 2011/133751 PCT/US20111/033396 mixture to the original volume prior to degassing. To the stirring mixture at 23.0 'C was charged degassed 50% w/w NaOH (143 mL) over 10 min followed by 1-bromo-2-chloroethane (44.7 g, 311.6 mmol) over 30 min. The reaction was analyzed by HPLC in 1 h intervals for % conversion. Before sampling, stirring was stopped and the phases allowed to separate. The top organic phase was sampled for analysis. When a % conversion > 99 % was observed (typically after 2.5 - 3 h), the reaction mixture was cooled to 10 'C and was charged with water (461 mL) at such a rate as to maintain a temperature < 25 'C. The temperature was adjusted to 20 - 25 'C and the phases separated. Note: sufficient time should be allowed for complete phase separation. The aqueous phase was extracted with MTBE (123 mL), and the combined organic phase was washed with 1 N HCI (163mL) and 5% NaCl (163 mL). The solution of (2,2 difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonitrile in MTBE was concentrated to 164 mL under vacuum at 40 - 50 'C. The solution was charged with ethanol (256 mL) and again concentrated to 164 mL under vacuum at 50 - 60 'C. Ethanol (256 mL) was charged and the mixture concentrated to 164 mL under vacuum at 50 - 60 'C. The resulting mixture was cooled to 20 - 25 'C and diluted with ethanol to 266 mL in preparation for the next step. 1 H NMR (500 MHz, DMSO) 6 7.43 (d, J= 8.4 Hz, 1H), 7.40 (d, J= 1.9 Hz, 1H), 7.30 (dd, J= 8.4, 1.9 Hz, 1H), 1.75 (m, 2H), 1.53 (in, 2H). [00203] Synthesis of 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid. F D 6 N NaOH F 0 D F 0 ' C N EtOH, 80 OC OH [00204] The solution of (2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonitrile in ethanol from the previous step was charged with 6 N NaOH (277 mL) over 20 min and heated to an internal temperature of 77 - 78 'C over 45 min. The reaction progress was monitored by HPLC after 16 h. Note: the consumption of both (2,2-difluoro-1,3-benzodioxol 5-yl)-cyclopropanecarbonitrile and the primary amide resulting from partial hydrolysis of (2,2 difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonitrile were monitored. When a % conversion > 99 % was observed (typically 100% conversion after 16 h), the reaction mixture was cooled to 25 'C and charged with ethanol (41 mL) and DCM (164 mL). The solution was -57- WO 2011/133751 PCT/US20111/033396 cooled to 10 'C and charged with 6 N HCl (290 mL) at such a rate as to maintain a temperature < 25 'C. After warming to 20 - 25 'C, the phases were allowed to separate. The bottom organic phase was collected and the top aqueous phase was back extracted with DCM (164 mL). Note: the aqueous phase was somewhat cloudy before and after the extraction due to a high concentration of inorganic salts. The organics were combined and concentrated under vacuum to 164 mL. Toluene (328 mL) was charged and the mixture condensed to 164 mL at 70 - 75 'C. The mixture was cooled to 45 'C, charged with MTBE (364 ml) and stirred at 60 'C for 20 min. The solution was cooled to 25 'C and polish filtered to remove residual inorganic salts. MTBE (123 ml) was used to rinse the reactor and the collected solids. The combined organics were transferred to a clean reactor in preparation for the next step. [00205] Isolation of 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid. EOI OH0 Toluene OH F 0 OH FO0 OH [002061 The solution of 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid from the previous step is concentrated under vacuum to 164 mL, charged with toluene (328 mL) and concentrated to 164 mL at 70 - 75 'C. The mixture was then heated to 100 - 105 'C to give a homogeneous solution. After stirring at that temperature for 30 min, the solution was cooled to 5 'C over 2 hours and maintained at 5 'C for 3 hours. The mixture was then filtered and the reactor and collected solid washed with cold 1:1 toluene/n-heptane (2 X 123 mL). The material was dried under vacuum at 55 'C for 17 hours to provide 1-(2,2-difluoro-1,3 benzodioxol-5-yl)-cyclopropanecarboxylic acid as an off-white crystalline solid. 1-(2,2 difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid was isolated in 79% yield from (2,2-difluoro-1,3-benzodioxol-5-yl)-acetonitrile (3 steps including isolation) and with an HPLC purity of 99.0% AUC. ESI-MS in/z calc. 242.04, found 241.58 (M+)j; 1 H NMR (500 MHz, DMSO) 6 12.40 (s, 1H), 7.40 (d, J= 1.6 Hz, IH), 7.30 (d, J= 8.3 Hz, IH), 7.17 (dd, J= 8.3, 1.7 Hz, 1H), 1.46 (in, 2H), 1.17 (in, 2H). [00207] Alternative Synthesis of the Acid Moiety -58- WO 2011/133751 PCT/US20111/033396 [00208] Synthesis of (2,2-difluoro-1,3-benzodioxol-5-yl)-methanol. 1. Vitride (2 equiv) PhCH 3 (10 vol) F XO 2. 10% aq (w/w) NaOH (4 equiv) FO F O CO 2 H 86-92% yield F O 14K OH [00209] Commercially available 2,2-difluoro-1,3-benzodioxole-5-carboxylic acid (1.0 eq) is slurried in toluene (10 vol). Vitride@ (2 eq) is added via addition funnel at a rate to maintain the temperature at 15-25 'C. At the end of addition the temperature is increased to 40 'C for 2 h then 10% (w/w) aq. NaOH (4.0 eq) is carefully added via addition funnel maintaining the temperature at 40-50 'C. After stirring for an additional 30 minutes, the layers are allowed to separate at 40 'C. The organic phase is cooled to 20 'C then washed with water (2 x 1.5 vol), dried (Na 2
SO
4 ), filtered, and concentrated to afford crude (2,2-difluoro-1,3 benzodioxol-5-yl)-methanol that is used directly in the next step. [00210] Synthesis of 5-chloromethyl-2,2-difluoro-1,3-benzodioxole. 1. SOCl 2 (1.5 equiv) DMAP (0.01 equiv) MTBE (5 vol) 2. water (4 vol) F I-Ir
FX
0 1 OH 82-100 % yield FO 'N0 CI [00211] (2,2-difluoro-1,3-benzodioxol-5-yl)-methanol (1.0 eq) is dissolved in MTBE (5 vol). A catalytic amount of DMAP (1 mol %) is added and SOCl 2 (1.2 eq) is added via addition funnel. The SOC1 2 is added at a rate to maintain the temperature in the reactor at 15-25 'C. The temperature is increased to 30 'C for 1 hour then cooled to 20 'C then water (4 vol) is added via addition funnel maintaining the temperature at less than 30 'C. After stirring for an additional 30 minutes, the layers are allowed to separate. The organic layer is stirred and 10% (w/v) aq. NaOH (4.4 vol) is added. After stirring for 15 to 20 minutes, the layers are allowed to separate. The organic phase is then dried (Na 2
SO
4 ), filtered, and concentrated to afford crude 5-chloromethyl-2,2-difluoro-1,3-benzodioxole that is used directly in the next step. -59- WO 2011/133751 PCT/US20111/033396 [00212] Synthesis of (2,2-difluoro-1,3-benzodioxol-5-yl)-acetonitrile. 1. NaCN (1.4 equiv) DMSO (3 vol) 30-40 degrees C 2. water (6 vol) FX0rf MTBE (4 vol) O 0CN F 0 -KK.-C F0 95-100% yield [00213] A solution of 5-chloromethyl-2,2-difluoro-1,3-benzodioxole (1 eq) in DMSO (1.25 vol) is added to a slurry of NaCN (1.4 eq) in DMSO (3 vol) maintaining the temperature between 30-40 'C. The mixture is stirred for 1 hour then water (6 vol) is added followed by MTBE (4 vol). After stirring for 30 min, the layers are separated. The aqueous layer is extracted with MTBE (1.8 vol). The combined organic layers are washed with water (1.8 vol), dried (Na 2 SO4, filtered, and concentrated to afford crude (2,2-difluoro-1,3-benzodioxol-5-yl) acetonitrile (95%) that is used directly in the next step. [00214] The remaining steps are the same as described above for the synthesis of the acid moiety. [00215] Amine Moiety [00216] Synthesis of 2-bromo-5-fluoro-4-nitroaniline. 0 2 N N NBS 0 2 N ;Br F NH2 EtOAc F NH 2 50% A flask was charged with 3-fluoro-4-nitroaniline (1.0 equiv) followed by ethyl acetate (10 vol) and stirred to dissolve all solids. N-Bromosuccinimide (1.0 equiv) was added as a portion-wise as to maintain internal temperature of 22 'C. At the end of the reaction, the reaction mixture was concentrated in vacuo on a rotavap. The residue was slurried in distilled water (5 vol) to dissolve and remove succinimide. (The succinimide can also be removed by water workup procedure.) The water was decanted and the solid was slurried in 2-propanol (5 vol) overnight. The resulting slurry was filtered and the wetcake was washed with 2 propanol, dried in vacuum oven at 50 'C overnight with N 2 bleed until constant weight was achieved. A yellowish tan solid was isolated (50% yield, 97.5% AUC). Other impurities -60- WO 2011/133751 PCT/US20111/033396 were a bromo-regioisomer (1.4% AUC) and a di-bromo adduct (1.1% AUC). 1 H NMR (500 MHz, DMSO) 6 8.19 (1 H, d, J= 8.1 Hz), 7.06 (br. s, 2 H), 6.64 (d, 1 H,.J= 14.3 Hz). [00217] Synthesis ofp-toluenesulfonic acid salt of (R)-1-((4-amino-2-bromo-5 fluorophenyl)amino)-3-(benzyloxy)propan-2-ol. 1) O OBn cat. Zn(Cl0 4
)
2 -2H 2 0 2 N t Br toluene, 80 0c H 3 N Br F NH 2 2) H 2 , Pt(S)/C F XNH IPAc OH TsO 3) TsOH-H 2 0 OBn DCM [00218] A thoroughly dried flask under N 2 was charged with the following: Activated powdered 4A molecular sieves (50 wt% based on 2-bromo-5-fluoro-4-nitroaniline), 2-Bromo-5 fluoro-4-nitroaniline (1.0 equiv), zinc perchlorate dehydrate (20 mol%), and toluene (8 vol). The mixture was stirred at room temperature for NMT 30 min. Lastly, (R)-benzyl glycidyl ether (2.0 equiv) in toluene (2 vol) was added in a steady stream. The reaction was heated to 80 0 C (internal temperature) and stirred for approximately 7 hours or until 2-Bromo-5-fluoro-4 nitroaniline was <5%AUC. [00219] The reaction was cooled to room temperature and Celite (50 wt%) was added, followed by ethyl acetate (10 vol). The resulting mixture was filtered to remove Celite and sieves and washed with ethyl acetate (2 vol). The filtrate was washed with ammonium chloride solution (4 vol, 20% w/v). The organic layer was washed with sodium bicarbonate solution (4 vol x 2.5% w/v). The organic layer was concentrated in vacuo on a rotovap. The resulting slurry was dissolved in isopropyl acetate (10 vol) and this solution was transferred to a Buchi hydrogenator. [00220] The hydrogenator was charged with 5wt% Pt(S)/C (1.5 mol%) and the mixture was stirred under N 2 at 30 'C (internal temperature). The reaction was flushed with N 2 followed by hydrogen. The hydrogenator pressure was adjusted to 1 Bar of hydrogen and the -61- WO 2011/133751 PCT/US20111/033396 mixture was stirred rapidly (>1200 rpm). At the end of the reaction, the catalyst was filtered through a pad of Celite and washed with dichloromethane (10 vol). The filtrate was concentrated in vacuo. Any remaining isopropyl acetate was chased with dichloromethane (2 vol) and concentrated on a rotavap to dryness. [00221] The resulting residue was dissolved in dichloromethane (10 vol). p Toluenesulfonic acid monohydrate (1.2 equiv) was added and stirred overnight. The product was filtered and washed with dichloromethane (2 vol) and suction dried. The wetcake was transferred to drying trays and into a vacuum oven and dried at 45 'C with N 2 bleed until constant weight was achieved. p-Toluenesulfonic acid salt of (R)-1-((4-amino-2-bromo-5 fluorophenyl)amino)-3-(benzyloxy)propan-2-ol was isolated as an off-white solid. [00222] Chiral purity was determined to be >97%ee. [00223] Synthesis of (3-Chloro-3-methylbut-1-ynyl)trimethylsilane. HCl neat OH /. CI TMS 90% TMS [00224] Propargyl alcohol (1.0 equiv) was charged to a vessel. Aqueous hydrochloric acid (37%, 3.75 vol) was added and stirring begun. During dissolution of the solid alcohol, a modest endotherm (5-6 C) is observed. The resulting mixture was stirred overnight (16 h), slowly becoming dark red. A 30 L jacketed vessel is charged with water (5 vol) which is then cooled to 10 'C. The reaction mixture is transferred slowly into the water by vacuum, maintaining the internal temperature of the mixture below 25 'C. Hexanes (3 vol) is added and the resulting mixture is stirred for 0.5 h. The phases were settled and the aqueous phase (pH < 1) was drained off and discarded. The organic phase was concentrated in vacuo using a rotary evaporator, furnishing the product as red oil. [00225] Synthesis of (4-(Benzyloxy)-3,3-dimethylbut-1-ynvl)trimethylsilane. 1. Mg TMS BnOCH 2 Cl TMS OBn [00226] Method A -62- WO 2011/133751 PCT/US20111/033396 [00227] All equivalent and volume descriptors in this part are based on a 2 50g reaction. Magnesium turnings (69.5 g, 2.86 mol, 2.0 equiv) were charged to a 3 L 4-neck reactor and stirred with a magnetic stirrer under nitrogen for 0.5 h. The reactor was immersed in an ice water bath. A solution of the propargyl chloride (250 g, 1.43 mol, 1.0 equiv) in THF (1.8 L, 7.2 vol) was added slowly to the reactor, with stirring, until an initial exotherm (-10 'C) was observed. The Grignard reagent formation was confirmed by IPC using 1 H-NMR spectroscopy. Once the exotherm subsided, the remainder of the solution was added slowly, maintaining the batch temperature <15 'C. The addition required ~3.5 h. The resulting dark green mixture was decanted into a 2 L capped bottle. [00228] All equivalent and volume descriptors in this part are based on a 500g reaction. A 22 L reactor was charged with a solution of benzyl chloromethyl ether (95%, 375 g, 2.31 mol, 0.8 equiv) in THF (1.5 L, 3 vol). The reactor was cooled in an ice-water bath. Two Grignard reagent batches prepared as described above were combined and then added slowly to the benzyl chloromethyl ether solution via an addition funnel, maintaining the batch temperature below 25 'C. The addition required 1.5 h. The reaction mixture was stirred overnight (16 h). [00229] All equivalent and volume descriptors in this part are based on a 1 kg reaction. A solution of 15% ammonium chloride was prepared in a 30 L jacketed reactor (1.5 kg in 8.5 kg of water, 10 vol). The solution was cooled to 5 'C. Two Grignard reaction mixtures prepared as described above were combined and then transferred into the ammonium chloride solution via a header vessel. An exotherm was observed in this quench, which was carried out at a rate such as to keep the internal temperature below 25 'C. Once the transfer was complete, the vessel jacket temperature was set to 25 'C. Hexanes (8 L, 8 vol) was added and the mixture was stirred for 0.5 h. After settling the phases, the aqueous phase (pH 9) was drained off and discarded. The remaining organic phase was washed with water (2 L, 2 vol). The organic phase was concentrated in vacuo using a 22 L rotary evaporator, providing the crude product as an orange oil. [00230] Method B -63- WO 2011/133751 PCT/US20111/033396 [00231] Magnesium turnings (106 g, 4.35 mol, 1.0 eq) were charged to a 22 L reactor and then suspended in THF (760 mL, 1 vol). The vessel was cooled in an ice-water bath such that the batch temperature reached 2 'C. A solution of the propargyl chloride (760 g, 4.35 mol, 1.0 equiv) in THF (4.5 L, 6 vol) was added slowly to the reactor. After 100 mL was added, the addition was stopped and the mixture stirred until a 13 'C exotherm was observed, indicating the Grignard reagent initiation. Once the exotherm subsided, another 500 mL of the propargyl chloride solution was added slowly, maintaining the batch temperature <20 'C. The Grignard reagent formation was confirmed by IPC using 'H-NMR spectroscopy. The remainder of the propargyl chloride solution was added slowly, maintaining the batch temperature <20 'C. The addition required ~1.5 h. The resulting dark green solution was stirred for 0.5 h. The Grignard reagent formation was confirmed by IPC using 1 H-NMR spectroscopy. Neat benzyl chloromethyl ether was charged to the reactor addition funnel and then added dropwise into the reactor, maintaining the batch temperature below 25 'C. The addition required 1.0 h. The reaction mixture was stirred overnight. The aqueous work-up and concentration was carried out using the same procedure and relative amounts of materials as in Method A to give the product as an orange oil. [00232] Syntheisis of 4-Benzyloxy-3,3-dimethylbut-1-yne. KOH TMS OBn 88% over OBn 2 steps [00233] A 30 L jacketed reactor was charged with methanol (6 vol) which was then cooled to 5 'C. Potassium hydroxide (85%, 1.3 equiv) was added to the reactor. A 15-20 'C exotherm was observed as the potassium hydroxide dissolved. The jacket temperature was set to 25 'C. A solution of 4-benzyloxy-3,3-dimethyl-1-trimethylsilylbut-1-yne (1.0 equiv) in methanol (2 vol) was added and the resulting mixture was stirred until reaction completion, as monitored by HPLC. Typical reaction time at 25 'C is 3-4 h. The reaction mixture is diluted with water (8 vol) and then stirred for 0.5 h. Hexanes (6 vol) was added and the resulting mixture was stirred for 0.5 h. The phases were allowed to settle and then the aqueous phase (pH 10-11) was drained off and discarded. The organic phase was washed with a solution of -64- WO 2011/133751 PCT/US20111/033396 KOH (85%, 0.4 equiv) in water (8 vol) followed by water (8 vol). The organic phase was then concentrated down using a rotary evaporator, yielding the title material as a yellow-orange oil. Typical purity of this material is in the 80% range with primarily a single impurity present. H NMR (400 MHz, C 6
D
6 ) 6 7.28 (d, 2 H, J= 7.4 Hz), 7.18 (t, 2 H, J= 7.2 Hz), 7.10 (d, 1H, J= 7.2 Hz), 4.35 (s, 2 H), 3.24 (s, 2 H), 1.91 (s, I H), 1.25 (s, 6 H). [00234] Synthesis of N-benzylglycolated-5-amino-2-(2-benzyloxy-1,1 dimethylethyl)-6-fluoroindole. [002351 Method A [00236] Synthesis of (R)-1-((4-amino-2-(4-(benzyloxy)-3,3-dimethylbut-1-yn-1-yl) 5-fluorophenyl)amino)-3-(benzyloxy)propan-2-ol. H2N Br OBn I OBn H 2 N F aNH OH Pd(OAc), dppb, F NH
K
2
CO
3 , Cul, water OH OBn OBn [00237] p-Toluenesulfonic acid salt of (R)-1-((4-amino-2-bromo-5 fluorophenyl)amino)-3-(benzyloxy)propan-2-ol was freebased by stirring the solid in dichloromethane (5 vol) and saturated NaHCO 3 solution (5 vol) until clear organic layer was achieved. The resulting layers were separated and the organic layer was washed with saturated NaHCO 3 solution (5 vol) followed by brine and concentrated in vacuo to obtain (R)- 1 -((4 amino-2-bromo-5-fluorophenyl)amino)-3-(benzyloxy)propan-2-ol free base as an oil. [00238] Palladium acetate (0.01 eq), dppb (0.015 eq), Cul (0.015 eq) and potassium carbonate (3 eq) are suspended in acetonitrile (1.2 vol). After stirring for 15 minutes, a solution of 4-benzyloxy-3,3-dimethylbut-1-yne (1.1 eq) in acetonitrile (0.2 vol) is added. The mixture is sparged with nitrogen gas for 1 h and then a solution of (R)-1 -((4-amino-2-bromo-5 fluorophenyl)amino)-3-(benzyloxy)propan-2-ol free base (1 eq) in acetonitrile (4.1 vol) is added. The mixture is sparged with nitrogen gas for another hour and then is heated to 80 'C. Reaction progress is monitored by HPLC and the reaction is usually complete within 3-5 h. The -65- WO 2011/133751 PCT/US20111/033396 mixture is cooled to room temperature and then filtered through Celite. The cake is washed with acetonitrile (4 vol). The combined filtrates are azeotroped to dryness and then the mixture is polish filtered into the next reactor. The acetonitrile solution of (R)-1-((4-amino-2-(4 (benzyloxy)-3,3-dimethylbut-1-yn-1-yl)-5-fluorophenyl)amino)-3-(benzyloxy)propan-2-ol thus obtained is used directly in the next procedure (cyclization) without further manipulation. [00239] Synthesis of N-benzylglycolated-5-amino-2-(2-benzyloxy-1,1 dimethylethyl)-6-fluoroindole.
H
2 N OBn
H
2 N O~n I (MeCN) 2 PdCl 2 F N F NH Cul OH OH OBn OBn [00240] Bis-acetonitriledichloropalladium (0.1 eq) and Cul (0.1 eq) are charged to the reactor and then suspended in a solution of (R)-1 -((4-amino-2-(4-(benzyloxy)-3,3-dimethylbut 1 -yn- 1-yl)-5 -fluorophenyl)amino)-3 -(benzyloxy)propan-2-ol obtained above (1 eq) in acetonitrile (9.5 vol total). The mixture is sparged with nitrogen gas for 1 h and then is heated to 80 'C. The reaction progress is monitored by HPLC and the reaction is typically complete within 1-3 h. The mixture is filtered through Celite and the cake is washed with acetonitrile. A solvent swap into ethyl acetate (7.5 vol) is performed. The ethyl acetate solution is washed with aqueous NH 3
-NH
4 CI solution (2 x 2.5 vol) followed by 10% brine (2.5 vol). The ethyl acetate solution is then stirred with silica gel (1.8 wt eq) and Si-TMT (0.1 wt eq) for 6 h. After filtration, the resulting solution is concentrated down. The residual oil is dissolved in DCM / heptane (4 vol) and then purified by column chromatography. The oil thus obtained is then crystallized from 25% EtOAc / heptane (4 vol). Crystalline (R)-1-(5-amino-2-(1-(benzyloxy)-2 methylpropan-2-yl)-6-fluoro- 1 H-indol- 1 -yl)-3 -(benzyloxy)propan-2-ol is typically obtained in 27-38% yield. 1 H NMR (400 MHz, DMSO) 6 7.38-7.34 (m, 4 H), 7.32-7.23 (m, 6 H), 7.21 (d, 1 H, J= 12.8 Hz), 6.77 (d, 1H, J= 9.0 Hz), 6.06 (s, 1 H), 5.13 (d, 1H, J= 4.9 Hz), 4.54 (s, 2 H), 4.46 (br. s, 2 H), 4.45 (s, 2 H), 4.33 (d, I H, J= 12.4 Hz), 4.09-4.04 (m, 2 H), 3.63 (d, 1H, J= -66- WO 2011/133751 PCT/US20111/033396 9.2 Hz), 3.56 (d, 1H, J= 9.2 Hz), 3.49 (dd, 1H, J= 9.8, 4.4 Hz), 3.43 (dd, 1H, J= 9.8, 5.7 Hz), 1.40 (s, 6 H). [00241] Synthesis of N-benzylglycolated-5-amino-2-(2-benzyloxy-1,1 dimethylethyl)-6-fluoroindole. [00242] Method B H Br OBn H 2 N 1.<- 0Bn F NHFOn F OH Pd(OAc)2 OH TsO dppb, K 2 C0 3 OBn MeCN OBn 2. (MeCN) 2 PdCl 2 MeCN, 80 1C 3. Silica gel filtration [00243] Palladium acetate (33 g, 0.04 eq), dppb (94 g, 0.06 eq), and potassium carbonate (1.5 kg, 3.0 eq) are charged to a reactor. The free based oil benzylglocolated 4 ammonium-2-bromo-5-flouroaniline (1.5 kg, 1.0 eq) was dissolved in acetonitrile (8.2 L, 4.1 vol) and then added to the reactor. The mixture was sparged with nitrogen gas for NLT 1 h. A solution of 4-benzyloxy-3,3-dimethylbut-1-yne (70%, 1.1 kg, 1.05 eq) in acetonitrile was added to the mixture which was then sparged with nitrogen gas for NLT 1 h. The mixture was heated to 80 'C and then stirred overnight. IPC by HPLC is carried out and the reaction is determined to be complete after 16 h. The mixture was cooled to ambient temperature and then filtered through a pad of Celite (228 g). The reactor and Celite pad were washed with acetonitrile (2 x 2 L, 2 vol). The combined phases are concentrated on a 22 L rotary evaporator until 8 L of solvent have been collected, leaving the crude product in 7 L (3.5 vol) of acetonitrile. [00244] Bis-acetonitriledichloropalladium (144 g, 0.15 eq) was charged to the reactor. The crude solution was transferred back into the reactor and the roto-vap bulb was washed with acetonitrile (4 L, 2 vol). The combined solutions were sparged with nitrogen gas for NLT I h. The reaction mixture was heated to 80 'C for NLT 16 h. In process control by HPLC shows complete consumption of starting material. The reaction mixture was filtered through Celite (300 g). The reactor and filter cake were washed with acetonitrile (3 L, 1.5 vol). The combined -67- WO 2011/133751 PCT/US20111/033396 filtrates were concentrated to an oil by rotary evaporation. The oil was dissolved in ethyl acetate (8.8 L, 4.4 vol). The solution was washed with 20% ammonium chloride (5 L, 2.5 vol) followed by 5% brine (5 L, 2.5 vol). Silica gel (2.5 kg, 1.8 wt. eq.) of silica gel was added to the organic phase, which was stirred overright. Deloxan THP II metal scavenger (358 g) and heptane (17.6 L) were added and the resuhling mixture was stirred for NLT 3 h. The mixture was filtered through a sintered glass funnel. The filter cake was washed with 30% ethyl acetate in heptane (25 L). The combined filtrates were concentrated under reduced pressure to give N benzylglycolated-5-amino-2-(2-benzyloxy- 1,1 -diinethylethyl)-6-fluoroindole as a brown paste (1.4 kg). [00245] Synthesis of Compoundi 1 [00246] Synthesis of benzyl protected Compound 1. F P SOc 2 F FO OH toluene F H ~ O N{ toHe 02 O B n F FO B n OH OH O Bn Ft4N, DCM, toluerre n [002471 1-(2,2-Difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid (1.3 equiv) was slurried in toluene (2.5 vol, based on I -(2,2-difluoro-1,3-benzodioxol-5-y) cyclopropanecarboxylic acid). Thionyl chloride (SOC12, 1.7 equiv) was added via addition funnel and the mixture was heated to 60 *(. The resulting mixture was stirred for 2 h. The toluene and the excess SOC12 were distilled off using rotavop. Additional toluene (2.5 vol, based on 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cy.'clopropanecarboxylic acid) was added and the mixture was distilled down to I vol of ioluene. A solution of (R)-1-(5-amino-2-(1 (benzyloxy)-2-methylpropan-2-yl)-6-fluoro-1H-indol-1-yl)-3-(benzyloxy)propan-2-ol (1 eq) and triethylamine (3 eq) in DCM (4 vol) is cooled to 0 *C. The acid chloride solution in toluene (1 vol) is added while maintaining the batch temperature below 10 *C. The reaction progress is monitored by HPLC, and the reaction is usually c:>mplete within minutes. After warming to 25 68 WO 2011/133751 PCT/US20111/033396 *C, the reaction mixture is washed with 5% NaHCO3 (3.5 vol), 1 M NaOH (3.5 vol) and 1 M HCI (5 vol). A solvent swap to into methaiol (2 ,ol) is performed and the resulting solution of (R)-N-(1-(3-(benzyloxy)-2-hydroxypropyl)-2-(1 -'"benzyloxy)-2-methylpropan-2-y1)-6-fluoro 1H-indo-5-yL)-1-(2,2-difluorobenzo[dJ[l.3]dioxol-5-yl)cyclopropanecarboxamide in methanol is used without further manipulation in the next srep (hydrogenolysis). [002481 Synthesis of Compound 1. H I-H OBn H 2 , Pd ! C F )CO,~>~ F 0,1) A OH 11C -MOH KI OH OBn Compound 1 OH [00249] 5% palladium on charcoal (-5C % wet, 0.01 eq) is charged to an appropriate hydrogenation vessel. The (R)-N-(1 -(3 -(be nzyloxy)-2-hydroxypropyl)-2-(I -(benzyloxy)-2 inethylpropan-2-yl)-6-fluoro- lH-indol-5-l )-I -(2 2-difluorobenzo[d][1,3]dioxol-5 yl)cyclopropanecarboxamide solution in nethanc1 (2 vol) obtained above is added carefully, followed by a 3 M solution of HCl in metthanol. The vessel is purged with nitrogen gas and then with hydrogen gas. The mixture is stirred vigorous sly until the reaction is complete, as determined by HPLC analysis. Typica[ reaction time is 3-5 h. The reaction mixture is filtered through Celite and the cake is washed witl] methanol (2 vol). A solvent swap into isopropanol (3 vol) is performed. Crude Compound i ; crystallized from 75% IPA-heptane (4 vol, ie. I vol heptane added to the 3 vol of IPA) and the resulting crystals are matured in 50% IPA-heptane (ie. 2 vol of heptane added to the mixture). Typical yields of compound 4 from the two-step acylation / hydrogenolysis procedure range from 68% to 84%. Compound 4 can be recrystallized from IPA-heptane following the sane procedure just described. [002501 Compound I may also b. prepared by one of several synthetic routes disclosed in US published patent application US20090131492, incorporated herein by reference. [002511 Table 10 below recites analytical data for Compound 1. Table 10. 69 WO 2011/133751 PCT/US20111/033396 MR (400.0 MHz, CD 3 CN) d 7.69 (d, J = 7.7 Hz, 1H), (d, J = 1.6 Hz, 1H), 7.39 (dd, J =1.7, 8.3 Hz, 1H), 7.31 (s, 1H), 7.27 (d, J = 8.3 Hz, 1H), 7.20 (d, J = 12.0 Hz, 1H), 6.34 (s, 1H), 1 521. 1.69 4.32 (d, J = 6.8 Hz, 2H), 4.15 -4.09 (in, 1H), 3.89 (dd, J = 6.0, 11.5 Hz, 1 H), 3.63 - 3.52 (in, 3H), 3.42 (d, J = 4.6 Hz, 1 H), 3.21 (dd, J = 6.2, 7.2 Hz, 1H), 3.04 (t, J = 5.8 Hz, 1H), 1.59 (dd, J = 3.8, 6.8 Hz, 2H), 1.44 (s, 3H), 1.33 (s, 3H) and 1.18 (dd, J = 3.7, 6.8 Hz, 2H) ppm. [002521 ASSAYS [00253] Assays for Detecting and Measuring AF508-CFTR Correction Properties of Compounds [002541 Membrane potential optical methods for assaying AF508-CFTR modulation properties of compounds [002551 The optical membrane potential assay utilized voltage-sensitive FRET sensors described by Gonzalez and Tsien (SE Gonzalez, J. E. and R. Y. Tsien (1995) "Voltage sensing by fluorescence resonance energy transfer in single cells" Biophys J 69(4): 1272-80, and Gonzalez, J. E. and R. Y. Tsien (1997) "Improved indicators of cell membrane potential that use fluorescence resonance energy transfer" Chem Biol 4(4): 269-77) in combination with instrumentation for measuring fluorescence changes such as the Voltage/Ion Probe Reader (VIPR) (See, Gonzalez, J. E., K. Oades, et al. (1999) "Cell-based assays and instrumentation for screening ion-channel targets" Drug Discov Today 4(9): 43 1-439). [002561 These voltage sensitive assays are based on the change in fluorescence resonant energy transfer (FRET) between the membrane-soluble, voltage-sensitive dye, DiSBAC 2 (3), and a fluorescent phospholipid, CC2-DMPE, which is attached to the outer leaflet of the plasma membrane and acts as a FRET donor. Changes in membrane potential (Vm) cause the negatively charged DiSBAC 2 (3) to redistribute across the plasma membrane and the amount of energy transfer from CC2-DMPE changes accordingly. The changes in fluorescence emission were monitored using VIPRI 11, which is an integrated liquid handler and fluorescent -70- WO 2011/133751 PCT/US20111/033396 detector designed to conduct cell-based screens in 96- or 384-well microtiter plates. [00257] 1. Identification of Correction Compounds [00258] To identify small molecules that correct the trafficking defect associated with AF508-CFTR; a single-addition HTS assay format was developed. The cells were incubated in serum-free medium for 16 hrs at 37 'C in the presence or absence (negative control) of test compound. As a positive control, cells plated in 384-well plates were incubated for 16 hrs at 27 'C to "temperature-correct" AF508-CFTR. The cells were subsequently rinsed 3X with Krebs Ringers solution and loaded with the voltage-sensitive dyes. To activate AF508-CFTR, 10 pM forskolin and the CFTR potentiator, genistein (20 gM), were added along with Cl-free medium to each well. The addition of Cl--free medium promoted Cl- efflux in response to AF508-CFTR activation and the resulting membrane depolarization was optically monitored using the FRET based voltage-sensor dyes. [00259] 2. Identification of Potentiator Conpounds [00260] To identify potentiators of AF508-CFTR, a double-addition HTS assay format was developed. During the first addition, a Cl--free medium with or without test compound was added to each well. After 22 sec, a second addition of Cl--free medium containing 2 - 10 tM forskolin was added to activate AF508-CFTR. The extracellular Cl- concentration following both additions was 28 mM, which promoted Cl- efflux in response to AF508-CFTR activation and the resulting membrane depolarization was optically monitored using the FRET-based voltage-sensor dyes.3. Solutions Bath Solution #1: (in mM) NaCl 160, KCI 4.5, CaC 2 2, MgCl 2 1, HEPES 10, pH 7.4 with NaOH. Chloride-free bath solution: Chloride salts in Bath Solution #1 are substituted with gluconate salts. CC2-DMPE: Prepared as a 10 mM stock solution in DMSO and stored at -20'C. -71- WO 2011/133751 PCT/US20111/033396 DiSBAC 2 (3): Prepared as a 10 mM stock in DMSO and stored at -20'C. [00262 4. Cell Culture [00263] NIH3T3 mouse fibroblasts stably expressing AF508-CFTR are used for optical measurements of membrane potential. The cells are maintained at 37 'C in 5% CO 2 and 90 % humidity in Dulbecco's modified Eagle's medium supplemented with 2 mM glutamine, 10 % fetal bovine serum, 1 X NEAA, p-ME, 1 X pen/strep, and 25 mM HEPES in 175 cm2 culture flasks. For all optical assays, the cells were seeded at 30,000/well in 384-well matrigel-coated plates and cultured for 2 hrs at 37 'C before culturing at 27 'C for 24 hrs for the potentiator assay. For the correction assays, the cells are cultured at 27 'C or 37 'C with and without compounds for 16 - 24 hours. [00264] Electrophysiological Assavs for assaving AF508-CFTR modulation properties ofcompounds [002651 1. Ussing Chamber Assav [00266] Using chamber experiments were performed on polarized epithelial cells expressing AF508-CFTR to further characterize the AF508-CFTR modulators identified in the optical assays. FRTAF 5 08-CFTR epithelial cells grown on Costar Snapwell cell culture inserts were mounted in an Ussing chamber (Physiologic Instruments, Inc., San Diego, CA), and the monolayers were continuously short-circuited using a Voltage-clamp System (Department of Bioengineering, University of Iowa, IA, and, Physiologic Instruments, Inc., San Diego, CA). Transepithelial resistance was measured by applying a 2-mV pulse. Under these conditions, the FRT epithelia demonstrated resistances of 4 KQ/ cm 2 or more. The solutions were maintained at 27 'C and bubbled with air. The electrode offset potential and fluid resistance were corrected using a cell-free insert. Under these conditions, the current reflects the flow of Cl- through AF508-CFTR expressed in the apical membrane. The Isc was digitally acquired using an MP100A-CE interface and AcqKnowledge software (v3.2.6; BIOPAC Systems, Santa Barbara, CA). [00267 2. Identification of Correction Compounds -72- WO 2011/133751 PCT/US20111/033396 [00268] Typical protocol utilized a basolateral to apical membrane Cl- concentration gradient. To set up this gradient, normal ringer was used on the basolateral membrane, whereas apical NaCl was replaced by equimolar sodium gluconate (titrated to pH 7.4 with NaOH) to give a large Cl- concentration gradient across the epithelium. All experiments were performed with intact monolayers. To fully activate AF508-CFTR, forskolin (10 gM) and the PDE inhibitor, IBMX (100 pM), were applied followed by the addition of the CFTR potentiator, genistein (50 pM). [00269] As observed in other cell types, incubation at low temperatures of FRT cells stably expressing AF508-CFTR increases the functional density of CFTR in the plasma membrane. To determine the activity of correction compounds, the cells were incubated with 10 pM of the test compound for 24 hours at 37'C and were subsequently washed 3X prior to recording. The cAMP- and genistein-mediated 'sc in compound-treated cells was normalized to the 27'C and 37'C controls and expressed as percentage activity. Preincubation of the cells with the correction compound significantly increased the cAMP- and genistein-mediated Isc compared to the 37'C controls. [00270] 3. Identification ofPotentiator Compounds [00271] Typical protocol utilized a basolateral to apical membrane Cl concentration gradient. To set up this gradient, normal ringers was used on the basolateral membrane and was permeabilized with nystatin (360 pg/ml), whereas apical NaCl was replaced by equimolar sodium gluconate (titrated to pH 7.4 with NaOH) to give a large Cl- concentration gradient across the epithelium. All experiments were performed 30 min after nystatin permeabilization. Forskolin (10 tM) and all test compounds were added to both sides of the cell culture inserts. The efficacy of the putative AF508-CFTR potentiators was compared to that of the known potentiator, genistein. [00272] 4. Solutions Basolateral solution (in mM): NaCl (135), CaCl 2 (1.2), MgCl2 (1.2), K 2
HPO
4 (2.4), KHPO 4 (0.6), N-2-hydroxyethylpiperazine N'-2-ethanesulfonic acid (HEPES) (10), and -73- WO 2011/133751 PCT/US20111/033396 dextrose (10). The solution was titrated to pH 7.4 with NaOH. Apical solution (in mM): Same as basolateral solution with NaCl replaced with Na Gluconate (135). [00273 5. Cell Culture [00274] Fisher rat epithelial (FRT) cells expressing AF508-CFTR (FR AF 5 08-CFTR) were used for Ussing chamber experiments for the putative AF508-CFTR modulators identified from our optical assays. The cells were cultured on Costar Snapwell cell culture inserts and cultured for five days at 37 'C and 5% CO 2 in Coon's modified Ham's F-12 medium supplemented with 5% fetal calf serum, 100 U/ml penicillin, and 100 pg/ml streptomycin. Prior to use for characterizing the potentiator activity of compounds, the cells were incubated at 27 'C for 16 48 hrs to correct for the AF508-CFTR. To determine the activity of corrections compounds, the cells were incubated at 27 'C or 37 'C with and without the compounds for 24 hours. [00275 6. Whole-cell recordings The macroscopic AF508-CFTR current (IAF508) in temperature- and test compound corrected NIH3T3 cells stably expressing AF508-CFTR were monitored using the perforated patch, whole-cell recording. Briefly, voltage-clamp recordings of IAF508 were performed at room temperature using an Axopatch 200B patch-clamp amplifier (Axon Instruments Inc., Foster City, CA). All recordings were acquired at a sampling frequency of 10 kHz and low pass filtered at 1 kHz. Pipettes had a resistance of 5 - 6 MQ when filled with the intracellular solution. Under these recording conditions, the calculated reversal potential for Cl- (Eci) at room temperature was -28 mV. All recordings had a seal resistance > 20 GO and a series resistance < 15 MQ. Pulse generation, data acquisition, and analysis were performed using a PC equipped with a Digidata 1320 A/D interface in conjunction with Clampex 8 (Axon Instruments Inc.). The bath contained < 250 pl of saline and was continuously perifused at a rate of 2 ml/min using a gravity-driven perfusion system. [00276] 7. Identification of Correction Compounds [00277] To determine the activity of correction compounds for increasing the density of -74- WO 2011/133751 PCT/US20111/033396 functional AF508-CFTR in the plasma membrane, we used the above-described perforated patch-recording techniques to measure the current density following 24-hr treatment with the correction compounds. To fully activate AF508-CFTR, 10 gM forskolin and 20 gM genistein were added to the cells. Under our recording conditions, the current density following 24-hr incubation at 27'C was higher than that observed following 24-hr incubation at 37 'C. These results are consistent with the known effects of low-temperature incubation on the density of AF508-CFTR in the plasma membrane. To determine the effects of correction compounds on CFTR current density, the cells were incubated with 10 pM of the test compound for 24 hours at 37'C and the current density was compared to the 27'C and 37'C controls (% activity). Prior to recording, the cells were washed 3X with extracellular recording medium to remove any remaining test compound. Preincubation with 10 pM of correction compounds significantly increased the cAMP- and genistein-dependent current compared to the 37'C controls. [00278 8. Identification ofPotentiator Compounds [00279] The ability of AF508-CFTR potentiators to increase the macroscopic AF508 CFTR Cl current (IAF508) in NIH3T3 cells stably expressing AF508-CFTR was also investigated using perforated-patch-recording techniques. The potentiators identified from the optical assays evoked a dose-dependent increase in IAF508 with similar potency and efficacy observed in the optical assays. In all cells examined, the reversal potential before and during potentiator application was around -30 mV, which is the calculated Eci (-28 mV). [00280] 9. Solutions Intracellular solution (in mM): Cs-aspartate (90), CsCl (50), MgCl 2 (1), HEPES (10), and 240 pg/ml amphotericin-B (pH adjusted to 7.35 with CsOH). Extracellular solution (in mM): N-methyl-D-glucamine (NMDG)-Cl (150), MgCl 2 (2), CaCl 2 (2), HEPES (10) (pH adjusted to 7.35 with HCl). [002811 10. Cell Culture [00282] NIH3T3 mouse fibroblasts stably expressing AF508-CFTR are used for whole -75- WO 2011/133751 PCT/US20111/033396 cell recordings. The cells are maintained at 37 OC in 5% CO 2 and 90 % humidity in Dulbecco's modified Eagle's medium supplemented with 2 m M glutarmine, 10 % fetal bovine serum, I X NEAA, p-ME, 1 X pen/strep, and 25 mM HEPES in 175 cm 2 culture flasks. For whole-cell recordings, 2,500 - 5,000 cells were seeded on pcly-L-lysine-coated glass coverslips and cultured for 24 - 48 irs at 27 'C before use to tes: the activity of potentiators; and incubated with or without the correction compound at 37 "C for measuring the activity of correctors. [002831 11. Single-channel recordings 1002841 The single-channel acti ities of temperature-corrected AF508-CFTR stably expressed in NIH3T3 cells and activities of poterstiator compounds were observed using excised inside-out membrane patch. Briefly, voltage-clamp recordings of single-channel activity were performed at room temperature with an Axopatch 200B patch-clamp amplifier (Axon Instruments Inc.). All recordings were acquired at a sampling frequency of 10 kHz and low pass filtered at 400 Hz. Patch pipettes were fabricated from Corning Kovar Sealing #7052 glass (World Precision Instruments, Inc., Sarasota, FL) and had a resistance of 5 - 8 MO when filled with the extracellular solution. The AF508-CFTF was activated after excision, by adding 1 mM Mg-ATP, and 75 nM of the cAMP-dependent protein kinase, catalytic subunit (PKA; Promega Corp. Madison, WI). After channel activity stabilized, the patch was perifused using a gravity driven microperfusion system. The inflow was placed adjacent to the patch, resulting in complete solution exchange within I - 2 sec. To maintain AF508-CFTR activity during the rapid perifusion, the nonspecific phosphatase inhibitor F (10 mM NaF) was added to the bath solution- Under these recording condition ;, channel activity remained constant throughout the duration of the patch recording (up to -60 ruin). Currents produced by positive charge moving from the intra- to extracellular solutions (anions moving in the opposite direction) are shown as positive currents. The pipette potential (V,,) was maintained at 80 mV. [002851 Channel activity was analyzed rom membrane patches containing 2 active channels. The maximum number of simultaneous openings determined the number of active channels during the course of an experiment. To determine the single-channel current amplitude, the data recorded from 120 sec of AF! 08-CFTR activity was filtered "off-line" at 100 Hz and then used to construct all-point amplitude histograms that were fitted with 76 WO 2011/133751 PCT/US20111/033396 multigaussian functions using Bio-Patch Analysis software (Bio-Logic Comp. France). The total microscopic current and open probability (P.) were determined from 120 sec of channel activity. The P. was determined using the Bio-Patch software or from the relationship P 0 = I/i(N), where I = mean current, i = single-channel current amplitude, and N = number of active channels in patch. [00286] 12. Solutions Extracellular solution (in mM): NMDG (150), aspartic acid (150), CaCl 2 (5), MgCl 2 (2), and HEPES (10) (pH adjusted to 7.35 with Tris base). Intracellular solution (in mM): NMDG-Cl (150), MgCl 2 (2), EGTA (5), TES (10), and Tris base (14) (pH adjusted to 7.35 with HCl). [002871 13. Cell Culture [002881 NIH3T3 mouse fibroblasts stably expressing AF508-CFTR are used for excised-membrane patch-clamp recordings. The cells are maintained at 37 'C in 5% CO 2 and 90 % humidity in Dulbecco's modified Eagle's medium supplemented with 2 mM glutamine, 10 % fetal bovine serum, I X NEAA, $-ME, 1 X pen/strep, and 25 mM HEPES in 175 cm 2 culture flasks. For single channel recordings, 2,500 - 5,000 cells were seeded on poly-L-lysine coated glass coverslips and cultured for 24 - 48 hrs at 27 'C before use. [00289] Using the procedures described above, the activity, i.e., EC50s, of Compound 1 has been measured and is shown in Table 11. Table 11. EC50 Bins: +++ <= 2.0 < ++ <= 5.0 C Perce ntActivty Bins: + <= 25.0 < ++< 100.0 < +++ Cmpd. No. Binned EC50 Binned MaxEfficacy 1I+ +++ -77-

Claims (15)

1. A method for preparing a compound of formula I: Gl X 5 wherein, independently for each occurrence: ring A is ; R 1 is independently selected from -Ri, -OR', -N(R') 2 , -NO 2 , halogen, -CN, -C_ 4 haloalkyl, -C 1 _ 4 haloalkoxy, -C(O)N(R ) 2 , -NRJC(O)Rj, -SORJ, -SO 2 RJ, -SO 2 N(R) 2 , -NRSO 2 RJ, -COR, -CO 2 RJ, -NRJSO 2 N(RJ) 2 , -COCORJ; 10 R is hydrogen or C 1 _ 6 aliphatic; X is CN or CO 2 R; R is C1_6 aliphatic or aryl; and m is an integer from 0 to 3 inclusive; comprising the steps of 15 a) reacting a compound of formula IA in a first organic solvent (R 1 ),m Hal IA wherein, independently for each occurrence: ring A is ; 20 R 1 is independently selected from -Ri, -ORJ, -N(RJ) 2 , -NO 2 , halogen, -CN, -C1_ 4 haloalkyl, -C1_ 4 haloalkoxy, -C(O)N(R ) 2 , -NRJC(O)Rj, -SORJ, -SO 2 RJ, -SO 2 N(R) 2 , -NRSO 2 RJ, -COR, -CO 2 RJ, -NRJSO 2 N(RJ) 2 , -COCORJ; R is hydrogen or C1_6 aliphatic; m is an integer from 0 to 3 inclusive; and 25 Hal is a halide; 79 with a compound of formula IB: 0 IB wherein RI is hydrogen or C1_6 aliphatic, to form a compound of formula IC: (R1)m A OR' 5 X IC wherein, independently for each occurrence: ring A is ; R 1 is independently selected from -Ri, -OR', -N(R') 2 , -NO 2 , halogen, -CN, -C 1 _ 4 haloalkyl, 10 -C1_ 4 haloalkoxy, -C(O)N(R ) 2 , -NRJC(O)Rj, -SORJ, -SO 2 RJ, -SO 2 N(R) 2 , -NRSO 2 RJ, -COR, -CO 2 RJ, -NRJSO 2 N(RJ) 2 , -COCORJ; R is hydrogen or C 1 _ 6 aliphatic; X is CN or CO 2 R; R is C1_6 aliphatic or aryl; and 15 m is an integer from 0 to 3 inclusive; and b) removing the -CO 2 R group from compound IC in a second organic solvent to form a compound of formula I.
2. The method of claim 1, wherein X is CN or CO 2 Et, Rj is a C 1 _ 6 aliphatic, and Hal is Br. 20
3. The method of any one of claims 1 or 2, wherein the first organic solvent is an aprotic solvent which is toluene and step a) is carried out at about 50 'C to 90 'C in the presence of a palladium catalyst selected from palladium(II)acetate, Pd(dppf)C1 2 , Pd(dba) 2 , tetrakis(triphenylphosphine)palladium(O) or tris(dibenzylideneacetone)dipalladium(0). 80
4. The method of any one of claims 1 to 3, wherein the second organic solvent is an aprotic solvent which is dimethylsulfoxide and step b) is carried out at about 55 'C to 95 'C in the presence of an inorganic acid.
5. The method of any one of claims 1 to 4, wherein step a) is carried out in the 5 presence of Pd(dba) 2 at about 70 'C and step b) is carried out at about 75 'C.
6. A method for preparing a compound of formula II: (R1)m A l Hal n wherein, independently for each occurrence: 10 ring A is ; Hal is a halide; R 1 is independently selected from -Ri, -OR, -N(RJ) 2 , -NO 2 , halogen, -CN, -C1_ 4 haloalkyl, -C1_ 4 haloalkoxy, -C(O)N(R ) 2 , -NRJC(O)Rj, -SORJ, -SO 2 RJ, -SO 2 N(R) 2 , -NRSO 2 RJ, -COR, -CO 2 RJ, -NRJSO 2 N(RJ) 2 , -COCORJ; 15 R is hydrogen or C 1 _ 6 aliphatic; m is an integer from 0 to 3 inclusive; and n is an integer from 1 to 4 inclusive; comprising the steps of a) reacting a compound of formula IIA in a first organic solvent (R 1 )m 20 Hal IIA wherein, independently for each occurrence: ring A is ; 81 R 1 is independently selected from -Ri, -OR', -N(R') 2 , -NO 2 , halogen, -CN, -C 1 _ 4 haloalkyl, -C1_ 4 haloalkoxy, -C(O)N(R ) 2 , -NRJC(O)Rj, -SORJ, -SO 2 RJ, -SO 2 N(R) 2 , -NRSO 2 RJ, -COR, -CO 2 RJ, -NRJSO 2 N(RJ) 2 , -COCORJ; R is hydrogen or C 1 _ 6 aliphatic; 5 m is an integer from 0 to 3 inclusive; and Hal is a halide; with a compound of formula IIB: 0 x AOR' JIB 10 wherein X is CN or CO 2 R; R is C 1 _ 6 aliphatic or aryl; and R is hydrogen or C1_6 aliphatic, to form a compound of formula IIC: (R1)m A| OR' x 15 JIC wherein, independently for each occurrence: ring A is ; R 1 is independently selected from -Ri, -ORJ, -N(RJ) 2 , -NO 2 , halogen, -CN, -C 1 _ 4 haloalkyl, -C1_ 4 haloalkoxy, -C(O)N(R ) 2 , -NRJC(O)Rj, -SORJ, -SO 2 RJ, -SO 2 N(R) 2 , 20 -NRSO 2 RJ, -COR, -CO 2 RJ, -NRJSO 2 N(RJ) 2 , -COCORJ; R is hydrogen or C 1 _ 6 aliphatic; X is CN or CO 2 R; R is C1_6 aliphatic or aryl; and m is an integer from 0 to 3 inclusive; 82 b) removing the -CO 2 RJ group from compound IIC in a second organic solvent to form a compound of formula I: Gl X 5 wherein, independently for each occurrence: ring A is ; R 1 is independently selected from -Ri, -ORJ, -N(RJ) 2 , -NO 2 , halogen, -CN, -C 1 _ 4 haloalkyl, -C 1 _ 4 haloalkoxy, -C(O)N(R ) 2 , -NRJC(O)Rj, -SOR, -SO 2 R, -SO 2 N(R) 2 , NRJSO 2 R, -CORJ, -CO 2 R, -NRSO 2 N(R) 2 , -COCORJ; 10 R is hydrogen or C 1 _ 6 aliphatic; X is CN or CO 2 R; R is C1_6 aliphatic or aryl; and m is an integer from 0 to 3 inclusive; c) reacting a compound of formula I with a compound of formula IID in 15 the presence of a base: Hal Hal q IID wherein, independently for each occurrence: Hal is a halide; and 20 q is an integer from 0 to 3 inclusive; to produce a compound of formula IIE: (R1)m A| x (In IIE 83 wherein, independently for each occurrence: F O F 0 ring A is ; R 1 is independently selected from -Ri, -OR', -N(R') 2 , -NO 2 , halogen, -CN, -C 1 _ 4 haloalkyl, -C1_ 4 haloalkoxy, -C(O)N(R ) 2 , -NRJC(O)Rj, -SOR, -SO 2 R, -SO 2 N(R) 2 , 5 NRJSO 2 R, -CORJ, -CO 2 R, -NRSO 2 N(R) 2 , -COCORJ; R is hydrogen or C 1 _ 6 aliphatic; m is an integer from 0 to 3 inclusive; X is CN or CO 2 R; R is C 1 _ 6 aliphatic or aryl; and 10 n is an integer from 1 to 4 inclusive; d) sequentially reacting a compound of formula IE with a hydroxide base and acid to form a compound of formula IIF: (R 1)m A l OH n IIF 15 wherein, independently for each occurrence: F O F 0 ring A is ; R 1 is independently selected from -Ri, -ORJ, -N(RJ) 2 , -NO 2 , halogen, -CN, -C1_ 4 haloalkyl, -C1_ 4 haloalkoxy, -C(O)N(R ) 2 , -NRJC(O)Rj, -SORJ, -SO 2 RJ, -SO 2 N(R) 2 , -NRSO 2 RJ, -COR, -CO 2 RJ, -NRJSO 2 N(RJ) 2 , -COCORJ; 20 R is hydrogen or C 1 _ 6 aliphatic; m is an integer from 0 to 3 inclusive; and n is an integer from 1 to 4 inclusive; and e) reacting a compound of formula IIF with a halogenating agent in a third organic solvent to form a compound of formula II. 25
7. The method of claim 6, wherein in step a), the first organic solvent is an aprotic solvent which is toluene, Hal is Br, X is CN or CO 2 Et, and Rj is Et. 84
8. The method of any one of claims 6 or 7, wherein in formula 1IC, I, and 1IE, m is 0, X is CN, and Rj is Et.
9. The method of any one of claims 6 to 8, wherein in step b), the second solvent is an aprotic solvent which is dimethylsulfoxide. 5
10. The method of any one of claims 6 to 9, wherein in step c), the base is an inorganic base.
11. The method of any one of claims 6 to 10, wherein in formula IID, one Hal is Cl and the other Hal is Br.
12. The method of any one of claims 6 to 11, wherein in step d), the base is NaOH 10 and the acid is HCl and the reaction with the base takes place at about 60 'C to 100 'C; and in step e) the third organic solvent is an aprotic solvent which is toluene, the halogenating agent is SOCl 2 , and step e) takes place at about 40 'C to 80 'C.
13. The method of any one of claims 6 to 12, wherein in formula IIF, m is 0, and n is 1; and in formula II, m is 0, n is 1, and Hal is Cl. 15
14. A compound of Formula I prepared according to the process of claim 1.
15. A compound of Formula II prepared according to the process of claim 6. Vertex Pharmaceuticals Incorporated Patent Attorneys for the Applicant/Nominated Person SPRUSON & FERGUSON
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Families Citing this family (89)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100074949A1 (en) 2008-08-13 2010-03-25 William Rowe Pharmaceutical composition and administration thereof
KR20060088537A (en) 2003-09-06 2006-08-04 버텍스 파마슈티칼스 인코포레이티드 Modulators of atp-binding cassette transporters
US7977322B2 (en) 2004-08-20 2011-07-12 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
CN101006076B (en) 2004-06-24 2010-09-29 沃泰克斯药物股份有限公司 Modulators of ATP-binding cassette transporters
AU2006279810B2 (en) 2005-08-11 2011-10-27 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
EP2404919B1 (en) 2005-11-08 2013-08-21 Vertex Pharmaceuticals Incorporated Heterocyclic compound useful as a modulator of ATP-binding cassette transporters.
DK3219705T3 (en) 2005-12-28 2020-04-14 Vertex Pharma PHARMACEUTICAL COMPOSITIONS OF THE AMORPHIC FORM OF N- [2,4-BIS (1,1-DIMETHYLETHYL) -5-HYDROXYPHENYL] -1,4-DIHYDRO-4-OXOQUINOLIN-3-CARBOXAMIDE
US7645789B2 (en) 2006-04-07 2010-01-12 Vertex Pharmaceuticals Incorporated Indole derivatives as CFTR modulators
PL2007756T3 (en) 2006-04-07 2016-01-29 Vertex Pharma Modulators of atp-binding cassette transporters
US10022352B2 (en) 2006-04-07 2018-07-17 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US8563573B2 (en) 2007-11-02 2013-10-22 Vertex Pharmaceuticals Incorporated Azaindole derivatives as CFTR modulators
US8969386B2 (en) 2007-05-09 2015-03-03 Vertex Pharmaceuticals Incorporated Modulators of CFTR
WO2009038913A2 (en) 2007-08-24 2009-03-26 Vertex Pharmaceuticals Incorporated Isothiazolopyridinones useful for the treatment of (inter alia) cystic fibrosis
EP2217572B1 (en) 2007-11-16 2013-11-06 Vertex Pharmaceuticals Incorporated Isoquinoline modulators of atp-binding cassette transporters
PL2225230T3 (en) 2007-12-07 2017-08-31 Vertex Pharmaceuticals Incorporated Solid forms of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl) benzoic acid
MX364936B (en) 2007-12-07 2019-05-15 Vertex Pharma Processes for producing cycloalkylcarboxiamido-pyridine benzoic acids.
US20100036130A1 (en) 2007-12-07 2010-02-11 Vertex Pharmaceuticals Incorporated Processes for producing cycloalkylcarboxamido-pyridine benzoic acids
ES2647531T3 (en) 2008-02-28 2017-12-22 Vertex Pharmaceuticals Incorporated Heteroaryl derivatives as CFTR modulators
EP2271621B1 (en) 2008-03-31 2013-11-20 Vertex Pharmaceuticals Incorporated Pyridyl derivatives as cftr modulators
AR073709A1 (en) 2008-09-29 2010-11-24 Vertex Pharma ACID DOSE UNITS 3- (6- (1- (2,2-DIFLUOROBENZENE (D) (1,3) DIOXOL-5-IL) CYCLOPROPANCARBOXAMIDE) -3-METHYLPIRIDIN-2-IL) BENZOIC
PT2408750E (en) 2009-03-20 2015-10-15 Vertex Pharma Process for making modulators of cystic fibrosis transmembrane conductance regulator
US8802868B2 (en) 2010-03-25 2014-08-12 Vertex Pharmaceuticals Incorporated Solid forms of (R)-1(2,2-difluorobenzo[D][1,3]dioxo1-5-yl)-N-(1-(2,3-dihydroxypropyl-6-fluoro-2-(1-hydroxy-2-methylpropan2-yl)-1H-Indol-5-yl)-Cyclopropanecarboxamide
RS61314B1 (en) * 2010-03-25 2021-02-26 Vertex Pharma Solid dispersion of amorphous form of (r)-1(2,2-difluorobenzo(d)(1,3)dioxol-5-yl)-n-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1h-indol-5-yl)-cyclopropanecarboxamide
NZ602838A (en) 2010-04-07 2015-06-26 Vertex Pharma Pharmaceutical compositions of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid and administration thereof
RS54783B1 (en) 2010-04-07 2016-10-31 Vertex Pharma Solid forms of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
SG184987A1 (en) * 2010-04-22 2012-11-29 Vertex Pharma Process of producing cycloalkylcarboxamido-indole compounds
MX357328B (en) 2011-11-08 2018-07-05 Vertex Pharma Modulators of atp-binding cassette transporters.
EP2819670A1 (en) 2012-02-27 2015-01-07 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administration thereof
AU2013290444B2 (en) 2012-07-16 2018-04-26 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions of (R)-1-(2,2-diflurorbenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl) cyclopropanecarboxamide and administration thereof
MX365950B (en) 2013-03-13 2019-06-19 Flatley Discovery Lab Llc Pyridazinone compounds and methods for the treatment of cystic fibrosis.
MX2016006118A (en) 2013-11-12 2016-07-21 Vertex Pharma Process of preparing pharmaceutical compositions for the treatment of cftr mediated diseases.
US10206877B2 (en) 2014-04-15 2019-02-19 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions for the treatment of cystic fibrosis transmembrane conductance regulator mediated diseases
GB201415381D0 (en) 2014-08-29 2014-10-15 Algipharma As Inhalable powder formulations of alginate oligomers
TWI735416B (en) 2014-10-06 2021-08-11 美商維泰克斯製藥公司 Modulators of cystic fibrosis transmembrane conductance regulator
RU2749213C2 (en) 2014-10-07 2021-06-07 Вертекс Фармасьютикалз Инкорпорейтед Co-crystals of transmembrane conduction regulator modulators in cystic fibrosis
US10302602B2 (en) 2014-11-18 2019-05-28 Vertex Pharmaceuticals Incorporated Process of conducting high throughput testing high performance liquid chromatography
EP3240539A4 (en) 2014-12-31 2018-07-25 Auspex Pharmaceuticals, Inc. Cyclopropanecarboxamide modulators of cystic fibrosis transmembrane conductance regulator
GB201504878D0 (en) 2015-03-23 2015-05-06 Algipharma As Use of alginate oligomers and CFTR modulators in the treatment of conditions associated with CFTR dysfuntion
CA2981495C (en) 2015-03-31 2023-09-26 Vertex Pharmaceuticals (Europe) Limited Deuterated vx-661
GB201517639D0 (en) 2015-10-06 2015-11-18 Algipharma As Use of alginate oligomers to treat or prevent microbial overgrowth in the intestinal tract
PL3394040T3 (en) * 2015-12-24 2022-05-02 The Regents Of The University Of California Cftr regulators and methods of use thereof
US10047077B2 (en) 2016-04-13 2018-08-14 Skyline Antiinfectives, Inc. Deuterated O-sulfated beta-lactam hydroxamic acids and deuterated N-sulfated beta-lactams
CN109803962B (en) 2016-09-30 2022-04-29 弗特克斯药品有限公司 Modulators of cystic fibrosis transmembrane conductance regulator proteins, and pharmaceutical compositions
MA54847A (en) 2016-12-09 2021-12-08 Vertex Pharma CRYSTALLINE FORM OF AN N-(PYRAZOL-4-YL)SULFONYL-6-(PYRAZOL-1-YL)-2-(PYRROLIDIN-1-YL)PYRIDINE-3-CARBOXAMIDE FOR TREATING VUD
US20180280349A1 (en) 2017-03-28 2018-10-04 Vertex Pharmaceuticals Incorporated Methods of treating cystic fibrosis in patients with residual function mutations
EP3634402A1 (en) 2017-06-08 2020-04-15 Vertex Pharmaceuticals Incorporated Methods of treatment for cystic fibrosis
US20210069174A1 (en) 2017-07-01 2021-03-11 Vertex Pharmaceuticals Incorporated Compositions and methods for treatment of cystic fibrosis
WO2019018353A1 (en) 2017-07-17 2019-01-24 Vertex Pharmaceuticals Incorporated Methods of treatment for cystic fibrosis
WO2019018395A1 (en) 2017-07-17 2019-01-24 Vertex Pharmaceuticals Incorporated Methods of treatment for cystic fibrosis
ES2912657T3 (en) 2017-08-02 2022-05-26 Vertex Pharma Processes for preparing pyrrolidine compounds
KR20200044873A (en) 2017-08-24 2020-04-29 더 리젠츠 오브 더 유니버시티 오브 캘리포니아 Eye pharmaceutical composition
AU2018351533B2 (en) 2017-10-19 2023-02-02 Vertex Pharmaceuticals Incorporated Crystalline forms and compositions of CFTR modulators
KR20200097293A (en) 2017-12-08 2020-08-18 버텍스 파마슈티칼스 인코포레이티드 Method for producing a modulator of cystic fibrosis transmembrane conduction modulator
TWI810243B (en) 2018-02-05 2023-08-01 美商維泰克斯製藥公司 Pharmaceutical compositions for treating cystic fibrosis
CN112004817B (en) 2018-02-15 2023-06-23 弗特克斯药品有限公司 Macrocyclic compounds as modulators of CFTR, pharmaceutical compositions thereof, their use and methods of preparation
US11414439B2 (en) 2018-04-13 2022-08-16 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator
LT3880197T (en) 2018-11-14 2023-05-10 Vertex Pharmaceuticals Incorporated Methods of treatment for cystic fibrosis
CA3067611A1 (en) 2019-01-15 2020-07-15 Apotex Inc. Processes for the preparation of tezacaftor and intermediates thereof
WO2020214921A1 (en) 2019-04-17 2020-10-22 Vertex Pharmaceuticals Incorporated Solid forms of modulators of cftr
WO2020256437A1 (en) * 2019-06-19 2020-12-24 주식회사 엘지화학 Preparation method for indole or indazole compound
CN114080383B (en) * 2019-06-19 2024-07-23 株式会社Lg化学 Process for preparing indole or indazole compounds
CN114599657A (en) 2019-08-14 2022-06-07 弗特克斯药品有限公司 Crystalline forms of a CFTR modulator
US20220313698A1 (en) 2019-08-14 2022-10-06 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
TW202115092A (en) 2019-08-14 2021-04-16 美商維泰克斯製藥公司 Modulators of cystic fibrosis transmembrane conductance regulator
TW202120517A (en) 2019-08-14 2021-06-01 美商維泰克斯製藥公司 Process of making cftr modulators
CN110437125B (en) * 2019-09-06 2021-03-12 苏州旺山旺水生物医药有限公司 Preparation method of Tezacaftor intermediate II
CN113121358A (en) * 2019-12-31 2021-07-16 阜新金特莱氟化学有限责任公司 Preparation method of 2-bromo-5-fluoro-4-nitroaniline
CN111187197B (en) * 2020-01-13 2021-10-01 苏州旺山旺水生物医药有限公司 Synthesis method of Tezacaftor intermediate
US20230057246A1 (en) * 2020-02-05 2023-02-23 Laurus Labs Limited Novel processes for preparation of tezacaftor
CR20230120A (en) 2020-08-07 2023-09-01 Vertex Pharma Modulators of cystic fibrosis transmembrane conductance regulator
IL300413A (en) 2020-08-13 2023-04-01 Vertex Pharma Crystalline forms of cftr modulators
IL301756A (en) 2020-10-07 2023-05-01 Vertex Pharma Modulators of cystic fibrosis transmembrane conductance regulator
US20230374038A1 (en) 2020-10-07 2023-11-23 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
WO2022076624A1 (en) 2020-10-07 2022-04-14 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
WO2022076628A1 (en) 2020-10-07 2022-04-14 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US20230373974A1 (en) 2020-10-07 2023-11-23 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
EP4225762A1 (en) 2020-10-07 2023-08-16 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
WO2022076622A2 (en) 2020-10-07 2022-04-14 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
WO2022076626A1 (en) 2020-10-07 2022-04-14 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
EP4225748A1 (en) 2020-10-07 2023-08-16 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US20230382924A1 (en) 2020-10-07 2023-11-30 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
MX2023006770A (en) 2020-12-10 2023-08-14 Vertex Pharma Methods of treatment for cystic fibrosis.
CN113657599B (en) * 2021-08-20 2024-05-28 北京航空航天大学 Accident cause and effect reasoning method, device, electronic equipment and readable storage medium
IL314449A (en) 2022-02-03 2024-09-01 Vertex Pharma Methods of treatment for cystic fibrosis
AU2023215372A1 (en) 2022-02-03 2024-08-22 Vertex Pharmaceuticals Incorporated Methods of preparing and crystalline forms of (6a,12a)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[ 12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol
WO2023154291A1 (en) 2022-02-08 2023-08-17 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
WO2023196429A1 (en) 2022-04-06 2023-10-12 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
WO2023224924A1 (en) 2022-05-16 2023-11-23 Vertex Pharmaceuticals Incorporated Solid forms of a macrocyclic compounds as cftr modulators and their preparation
WO2023224931A1 (en) 2022-05-16 2023-11-23 Vertex Pharmaceuticals Incorporated Methods of treatment for cystic fibrosis

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002011883A1 (en) * 2000-08-07 2002-02-14 Yale University CATALYST FOR AROMATIC C-O, C-N, and C-C BOND FORMATION
WO2002012236A1 (en) * 2000-08-04 2002-02-14 Bayer Cropscience Ag Substituted triazolopyrid(az)ines as plant treatment agents (herbicides)
EP1864978A1 (en) * 2005-03-28 2007-12-12 Toyama Chemical Co., Ltd. Process for production of 1-(3-(2-(1-benzothiophen-5-yl)- ethoxy)propyl)azetidin-3-ol or salts thereof
US20090131492A1 (en) * 2006-04-07 2009-05-21 Ruah Sara S Hadida Indole derivatives as CFTR modulators

Family Cites Families (324)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL7605382A (en) * 1975-06-04 1976-12-07 Sumitomo Chemical Co PROCESS FOR PREPARING INDOLE DERIVATIVES.
JPS5328173A (en) * 1976-08-06 1978-03-16 Zenyaku Kogyo Kk Novel phenylmethanenitro compound and its preparation
DE2735133C2 (en) 1977-08-04 1981-10-15 Universität Karlsruhe Institut für Elektrotechnische Grundlagen der Informatik, 7500 Karlsruhe Memory cell for non-destructive reading with 2 Josephson contacts
US4138397A (en) 1978-02-27 1979-02-06 Richardson-Merrell Inc. 6-(2,3-Dihydro-5-benzofuranyl)acetamido penicillin derivatives
GB8524157D0 (en) 1984-10-19 1985-11-06 Ici America Inc Heterocyclic amides
JPS61103861A (en) * 1984-10-27 1986-05-22 Nitto Kasei Kk Preparation of aryl-substituted cyanoacetic acid ester
US5304121A (en) 1990-12-28 1994-04-19 Boston Scientific Corporation Drug delivery system making use of a hydrogel polymer coating
US5886026A (en) 1993-07-19 1999-03-23 Angiotech Pharmaceuticals Inc. Anti-angiogenic compositions and methods of use
GB9317764D0 (en) 1993-08-26 1993-10-13 Pfizer Ltd Therapeutic compound
US5510379A (en) 1994-12-19 1996-04-23 Warner-Lambert Company Sulfonate ACAT inhibitors
US6099562A (en) 1996-06-13 2000-08-08 Schneider (Usa) Inc. Drug coating with topcoat
JPH10213820A (en) 1997-01-31 1998-08-11 Canon Inc Liquid crystal element and liquid crystal device
WO1998047868A1 (en) 1997-04-18 1998-10-29 Smithkline Beecham Plc Heterocycle-containing urea derivatives as 5ht1a, 5ht1b and 5ht1d receptor antagonists
DE69831233T2 (en) * 1997-06-21 2006-06-01 Roche Diagnostics Gmbh BARBITULE DERIVATIVES WITH ANTIMETASTATIC AND ANTITUMORIC EFFECT
DK0901786T3 (en) 1997-08-11 2007-10-08 Pfizer Prod Inc Solid pharmaceutical dispersions with increased bioavailability
US20020017295A1 (en) 2000-07-07 2002-02-14 Weers Jeffry G. Phospholipid-based powders for inhalation
ATE249219T1 (en) 1997-12-11 2003-09-15 Iaf Biochem Int ANTIVIRAL COMPOUNDS
US6426331B1 (en) 1998-07-08 2002-07-30 Tularik Inc. Inhibitors of STAT function
AUPP609198A0 (en) 1998-09-22 1998-10-15 Curtin University Of Technology Use of non-peptidyl compounds for the treatment of insulin related ailments
EP1035115B1 (en) 1999-02-24 2004-09-29 F. Hoffmann-La Roche Ag 4-Phenylpyridine derivatives and their use as NK-1 receptor antagonists
ATE329920T1 (en) 1999-09-10 2006-07-15 Novo Nordisk As MODULATORS OF PROTEIN TYROSINE PHOSPHATASE (PTPASES)
WO2001019831A1 (en) 1999-09-10 2001-03-22 Novo Nordisk A/S MODULATORS OF PROTEIN TYROSINE PHOSPHATASES (PTPases)
AUPQ288499A0 (en) 1999-09-16 1999-10-07 Biota Scientific Management Pty Ltd Antiviral agents
US6514964B1 (en) 1999-09-27 2003-02-04 Amgen Inc. Fused cycloheptane and fused azacycloheptane compounds and their methods of use
IT1315267B1 (en) 1999-12-23 2003-02-03 Novuspharma Spa DERIVATIVES OF 2- (1H-INDOL-3-IL) -2-OXO-ACETAMIDES FOR ANTI-TUMOR ACTIVITY
TWI284639B (en) 2000-01-24 2007-08-01 Shionogi & Co A compound having thrombopoietin receptor agonistic effect
US6777400B2 (en) 2000-08-05 2004-08-17 Smithkline Beecham Corporation Anti-inflammatory androstane derivative compositions
TWI259180B (en) 2000-08-08 2006-08-01 Hoffmann La Roche 4-Phenyl-pyridine derivatives
AR030357A1 (en) 2000-08-18 2003-08-20 Lundbeck & Co As H DERIVATIVES 4 -, 5 -, 6 - AND 7-INDOL
US6550895B1 (en) 2000-10-20 2003-04-22 Silverbrook Research Pty Ltd Moving nozzle ink jet with inlet restriction
DE60134679D1 (en) 2000-10-20 2008-08-14 Eisai R&D Man Co Ltd Nitrogen-containing aromatic heterocycles
EP1217000A1 (en) 2000-12-23 2002-06-26 Aventis Pharma Deutschland GmbH Inhibitors of factor Xa and factor VIIa
GB0102109D0 (en) 2001-01-26 2001-03-14 Syngenta Ltd Chemical process
US20100074949A1 (en) 2008-08-13 2010-03-25 William Rowe Pharmaceutical composition and administration thereof
EP1383799A4 (en) 2001-04-10 2008-08-06 Transtech Pharma Inc Probes, systems and methods for drug discovery
JP4535680B2 (en) 2001-04-16 2010-09-01 エーザイ・アール・アンド・ディー・マネジメント株式会社 New 1H-indazole compounds
NZ528752A (en) 2001-06-28 2006-06-30 Pfizer Prod Inc Triamide-substituted indoles, benzofuranes and benzothiophenes as inhibitors of microsomal triglyceride transfer protein (MTP) and/or apolipoprotein B (APO B) secretion
WO2003007945A1 (en) 2001-07-20 2003-01-30 Boehringer Ingelheim (Canada) Ltd. Viral polymerase inhibitors
AUPR738301A0 (en) 2001-08-30 2001-09-20 Starpharma Limited Chemotherapeutic agents
JP4343690B2 (en) 2001-11-13 2009-10-14 メルク フロスト カナダ リミテツド Cyanoalkylamino derivatives as protease inhibitors
CZ2004747A3 (en) 2001-12-21 2004-11-10 Novo Nordisk A/S Amide derivatives functioning as GK activators
US7074805B2 (en) 2002-02-20 2006-07-11 Abbott Laboratories Fused azabicyclic compounds that inhibit vanilloid receptor subtype 1 (VR1) receptor
US20030158188A1 (en) 2002-02-20 2003-08-21 Chih-Hung Lee Fused azabicyclic compounds that inhibit vanilloid receptor subtype 1 (VR1) receptor
AU2003228744A1 (en) 2002-04-29 2003-11-17 The Ohio State University Inhibition of protein tyrosine phosphatases and sh2 domains by a neutral phosphotyrosine mimetic
MXPA05000130A (en) 2002-06-27 2005-02-17 Novo Nordisk As Aryl carbonyl derivatives as therapeutic agents.
WO2004007472A1 (en) 2002-07-10 2004-01-22 Ono Pharmaceutical Co., Ltd. Ccr4 antagonist and medicinal use thereof
TWI244393B (en) 2002-08-06 2005-12-01 Idenix Pharmaceuticals Inc Crystalline and amorphous forms of beta-L-2'-deoxythymidine
RU2005111225A (en) 2002-09-18 2005-08-27 Оно Фармасьютикал Ко., Лтд. (Jp) DERIVATIVES OF TRIAZASPIRO [5.5] UNDECAN AND MEDICINES CONTAINING THEM AS AN ACTIVE INGREDIENT
MXPA05003366A (en) 2002-09-30 2005-10-05 Univ California Cystic fibrosis transmembrane conductance regulator protein inhibitors and uses thereof.
JP2004131393A (en) 2002-10-08 2004-04-30 Kowa Co Readily eluting pharmaceutical preparation
US20050215614A1 (en) 2002-10-15 2005-09-29 Rigel Pharmaceuticals, Inc. Substituted indoles and their use as hcv inhibitors
FR2846327B1 (en) 2002-10-25 2006-03-24 Merck Sante Sas N-BENZODIOXOLYL, N-BENZODIOXANYL AND N-BENZODIOXEPINYL ARYLCARBOXAMIDE DERIVATIVES USEFUL IN THE TREATMENT OF DYSLIPIDEMIA AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME
CA2504044A1 (en) 2002-11-01 2004-05-21 Merck & Co., Inc. Carbonylamino-benzimidazole derivatives as androgen receptor modulators
DE10251019A1 (en) 2002-11-02 2004-05-19 Aventis Pharma Deutschland Gmbh New pyrimidine-4,6-dicarboxamide derivatives, are selective collagenase inhibitors useful e.g. for treating degenerative joint diseases, connective tissue disorders or cancer
PL375044A1 (en) 2002-11-02 2005-11-14 Sanofi-Aventis Deutschland Gmbh Novel pyrimidine-4,6-dicarboxamides for the selective inhibition of collagenases
US20040146941A1 (en) 2002-11-04 2004-07-29 Biliang Zhang Chemical encoding technology for combinatorial synthesis
WO2004056744A1 (en) 2002-12-23 2004-07-08 Janssen Pharmaceutica N.V. Adamantyl acetamides as hydroxysteroid dehydrogenase inhibitors
DE10300017A1 (en) 2003-01-03 2004-07-15 Aventis Pharma Deutschland Gmbh Selective MMP 13 inhibitors
CA2512582C (en) 2003-01-08 2014-07-08 University Of Washington Antibacterial agents
US6933311B2 (en) 2003-02-11 2005-08-23 Abbott Laboratories Fused azabicyclic compounds that inhibit vanilloid receptor subtype 1 (VR1) receptor
ATE450533T1 (en) 2003-02-14 2009-12-15 Glaxo Group Ltd CARBOXAMIDE DERIVATIVES
DE10306941A1 (en) 2003-02-18 2004-08-26 Merck Patent Gmbh New indolyl-substituted benzofuranyloxy-alkylamine derivatives, are 5-hydroxytryptamine reuptake inhibitors useful e.g. as anxiolytic, antidepressant, neuroleptic and/or antihypertensive agents
EP1601657A1 (en) 2003-03-12 2005-12-07 Vertex Pharmaceuticals Incorporated Pyrazole modulators of atp-binding cassette transporters
DE10315377A1 (en) 2003-04-03 2004-10-14 Merck Patent Gmbh New carbonyl-substituted carbocyclic or heterocyclic compounds, are factor Xa and factor VIIa inhibitors useful e.g. for treating thrombosis, myocardial infarction, arteriosclerosis, inflammation or tumors
WO2004087646A2 (en) 2003-04-03 2004-10-14 Merck Patent Gmbh Pyrrolidino-1,2-dicarboxy-1-(phenylamide)-2-(4-(3-oxo-morpholino-4-yl)-phenylamide) derivatives and related compounds for use as inhibitors of coagulation factor xa in the treatment of thrombo-embolic diseases
US20050164951A1 (en) 2003-04-03 2005-07-28 The Regents Of The University Of California Inhibitors for the soluble epoxide hydrolase
ATE482747T1 (en) 2003-04-11 2010-10-15 High Point Pharmaceuticals Llc NEW AMIDE DERIVATIVES AND THEIR PHARMACEUTICAL USES
ES2770035T3 (en) 2003-04-11 2020-06-30 Ptc Therapeutics Inc 1,2,4-Oxadiazole benzoic acid compound and its use for senseless suppression and treatment of diseases
WO2004110352A2 (en) 2003-05-16 2004-12-23 The Regents Of The University Of California Compounds having activity in increasing ion transport by mutant-cftr and uses thereof
EP1646615B1 (en) 2003-06-06 2009-08-26 Vertex Pharmaceuticals Incorporated Pyrimidine derivatives as modulators of atp-binding cassette transporters
WO2005002519A2 (en) 2003-06-27 2005-01-13 Henry M.Jackson Foundation For The Advancement Of Military Medicine, Inc. Amphiphilic pyridinium compounds, method of making and use thereof
US20050113576A1 (en) 2003-08-05 2005-05-26 Chih-Hung Lee Fused azabicyclic compounds that inhibit vanilloid receptor subtype 1 (VR1) receptor
MXPA06001738A (en) 2003-08-15 2006-05-12 Lundbeck & Co As H Cyclopropyl derivatives as nk3 receptor antagonists.
KR20060088537A (en) 2003-09-06 2006-08-04 버텍스 파마슈티칼스 인코포레이티드 Modulators of atp-binding cassette transporters
US20050070718A1 (en) 2003-09-30 2005-03-31 Abbott Gmbh & Co. Kg Heteroaryl-substituted 1,3-dihydroindol-2-one derivatives and medicaments containing them
JP2007509044A (en) 2003-10-08 2007-04-12 バーテックス　ファーマシューティカルズ　インコーポレイテッド Modulator of ATP binding cassette transporter containing cycloalkylpyranyl group
WO2005037802A1 (en) * 2003-10-16 2005-04-28 Sankyo Company, Limited 5-arylpyrimidine derivative
JPWO2005040135A1 (en) 2003-10-24 2007-03-08 小野薬品工業株式会社 Anti-stress drugs and their medicinal uses
JP4869072B2 (en) 2003-11-14 2012-02-01 バーテックス ファーマシューティカルズ インコーポレイテッド Thiazoles and oxazoles useful as modulators of ATP binding cassette transporters
GB0330043D0 (en) 2003-12-24 2004-01-28 Pharmacia Italia Spa Pyrrolo [2,3-b] pyridine derivatives active as kinase inhibitors process for their preparation and pharmaceutical compositions comprising them
US8759335B2 (en) 2004-01-30 2014-06-24 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US7977322B2 (en) 2004-08-20 2011-07-12 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
CA2553040A1 (en) 2004-02-02 2005-08-18 Ambrx, Inc. Modified human four helical bundle polypeptides and their uses
WO2005094374A2 (en) 2004-03-30 2005-10-13 The Regents Of The University Of California Hydrazide-containing cftr inhibitor compounds and uses thereof
US20050222271A1 (en) 2004-03-31 2005-10-06 Le Huang Novel amorphous form of memantine hydrochloride
FR2868417B1 (en) 2004-04-02 2006-06-23 Rhodia Chimie Sa PROCESS FOR FORMING CARBON-CARBON BOND
CA2568499A1 (en) 2004-06-01 2005-12-15 Tm Bioscience Corporation Method of detecting cystic fibrosis associated mutations
EP1765347A4 (en) 2004-06-04 2008-10-01 Univ California Compounds having activity in increasing ion transport by mutant-cftr and uses thereof
US20140343098A1 (en) 2004-06-24 2014-11-20 Vertex Pharmaceuticals Incorporated Modulators of atp-binding cassette transporters
US8354427B2 (en) 2004-06-24 2013-01-15 Vertex Pharmaceutical Incorporated Modulators of ATP-binding cassette transporters
CN101006076B (en) 2004-06-24 2010-09-29 沃泰克斯药物股份有限公司 Modulators of ATP-binding cassette transporters
CA2572292A1 (en) 2004-07-02 2006-02-09 Advancis Pharmaceutical Corporation Tablet for pulsed delivery
GB0416730D0 (en) 2004-07-27 2004-09-01 Novartis Ag Organic compounds
MX2007001215A (en) 2004-08-06 2007-04-17 Otsuka Pharma Co Ltd Aromatic compounds.
DE102004047254A1 (en) 2004-09-29 2006-04-13 Merck Patent Gmbh carbonyl
CA2583177A1 (en) 2004-10-13 2006-04-27 Ptc Therapeutics, Inc. Compounds for nonsense suppression, and methods for their use
NZ554555A (en) 2004-10-20 2011-09-30 Univ California Cyclohexyl-urea derivatives as improved inhibitors for the soluble epoxide hydrolase
US20080051418A1 (en) 2004-11-26 2008-02-28 Tsuyoshi Maekawa Arylalkanoic Acid Derivative
NZ560513A (en) 2005-02-25 2010-07-30 Ono Pharmaceutical Co Indole compound and use thereof
EP1865949B1 (en) 2005-03-11 2012-11-14 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
KR20070114820A (en) 2005-03-18 2007-12-04 더 리젠츠 오브 더 유니버시티 오브 캘리포니아 Compounds having activity in correcting mutant-cftr processing and uses thereof
US20100120789A1 (en) 2005-03-24 2010-05-13 Nigel Vicker Compound
US7402596B2 (en) 2005-03-24 2008-07-22 Renovis, Inc. Bicycloheteroaryl compounds as P2X7 modulators and uses thereof
GB0506133D0 (en) 2005-03-24 2005-05-04 Sterix Ltd Compound
JP2006282534A (en) 2005-03-31 2006-10-19 Fuji Photo Film Co Ltd Preparation method of amides
NZ562197A (en) 2005-04-08 2010-09-30 Ptc Therapeutics Inc Compositions of an orally active 1,2,4-oxadiazole for nonsense mutation suppression therapy
US20070032475A1 (en) 2005-04-15 2007-02-08 Ye Xiaocong M Novel compounds useful for bradykinin B1 receptor antagonism
CA2609392A1 (en) 2005-05-24 2006-11-30 Vertex Pharmaceuticals Incorporated Modulators of atp-binding cassette transporters
AU2006279810B2 (en) 2005-08-11 2011-10-27 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
CN101287732A (en) 2005-08-11 2008-10-15 沃泰克斯药物股份有限公司 Modulators of cystic fibrosis transmembrane conductance regulator
AU2006297414A1 (en) * 2005-09-29 2007-04-12 Wyeth 1- (1H- indol- 1-yl) -3- (methylamino) -1- phenylpropan-2-ol derivatives and related compounds as modulators of the monoamine reuptake for the treatment of vasomotor symptoms (VMS)
US8314256B2 (en) 2005-10-06 2012-11-20 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
JP2009514875A (en) 2005-11-02 2009-04-09 サイトキネティクス・インコーポレーテッド Chemicals, compositions and methods
EP2404919B1 (en) 2005-11-08 2013-08-21 Vertex Pharmaceuticals Incorporated Heterocyclic compound useful as a modulator of ATP-binding cassette transporters.
US20120232059A1 (en) 2005-11-08 2012-09-13 Vertex Pharmaceuticals Incorporated Modulators of ATP-Binding Cassette Transporters
GB0525144D0 (en) 2005-12-09 2006-01-18 Novartis Ag Organic compounds
DK1966214T3 (en) * 2005-12-21 2017-02-13 Janssen Pharmaceutica Nv TRIAZOLPYRIDAZINES AS TYROSINKINASA MODULATORS
JP2009521468A (en) 2005-12-24 2009-06-04 バーテックス ファーマシューティカルズ インコーポレイテッド Quinolin-4-one derivatives as regulators of ABC transporters
EP1974212A1 (en) 2005-12-27 2008-10-01 Vertex Pharmaceuticals Incorporated Compounds useful in cftr assays and methods therewith
JP5165586B2 (en) 2005-12-28 2013-03-21 バーテックス ファーマシューティカルズ インコーポレイテッド 1- (Benzo [d] [1,3] dioxol-5-yl) -N- (phenyl) cyclopropane-carboxamide derivatives and related as modulators of ATP binding cassette transporters for the treatment of cystic fibrosis Compound
DK3219705T3 (en) 2005-12-28 2020-04-14 Vertex Pharma PHARMACEUTICAL COMPOSITIONS OF THE AMORPHIC FORM OF N- [2,4-BIS (1,1-DIMETHYLETHYL) -5-HYDROXYPHENYL] -1,4-DIHYDRO-4-OXOQUINOLIN-3-CARBOXAMIDE
US7671221B2 (en) 2005-12-28 2010-03-02 Vertex Pharmaceuticals Incorporated Modulators of ATP-Binding Cassette transporters
TW200808723A (en) 2006-03-13 2008-02-16 Univ California Conformationally restricted urea inhibitors of soluble epoxide hydrolase
RS20090406A (en) 2006-03-20 2010-12-31 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions
EP2001498A4 (en) 2006-03-20 2013-01-23 Vertex Pharma Pharmaceutical compositions
WO2007111994A2 (en) 2006-03-22 2007-10-04 Syndexa Pharmaceuticals Corporation Compounds and methods for treatment of disorders associated with er stress
US10022352B2 (en) 2006-04-07 2018-07-17 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
PL2007756T3 (en) 2006-04-07 2016-01-29 Vertex Pharma Modulators of atp-binding cassette transporters
ATE534383T1 (en) 2006-05-12 2011-12-15 Vertex Pharma COMPOSITIONS OF N-Ä2,4-BIS(1,1-DIMETHYLETHYL)-5-HYDROXYPHENYLÜ-1,4-DIHYDRO-4-OXOCINOLIN-3-CARBOXAMIDE
WO2007146712A2 (en) 2006-06-09 2007-12-21 Kemia, Inc. Therapy using cytokine inhibitors
WO2008020227A2 (en) 2006-08-17 2008-02-21 Astrazeneca Ab Antibacterial pyrrolecarboxamides
WO2008029168A2 (en) 2006-09-08 2008-03-13 Summit Corporation Plc Treatment of duchenne muscular dystrophy
WO2008029152A2 (en) 2006-09-08 2008-03-13 Summit Corporation Plc Treatment of duchenne muscular dystrophy
BRPI0717317A2 (en) * 2006-10-23 2013-10-22 Sgx Pharmaceuticals Inc MODULARS OF TRIAZALOPYRIDAZINE PROTEIN KINASE
US8563573B2 (en) 2007-11-02 2013-10-22 Vertex Pharmaceuticals Incorporated Azaindole derivatives as CFTR modulators
CN103159760B (en) 2006-11-03 2016-06-08 沃泰克斯药物股份有限公司 As the 7-azaindole derivatives of CFTR adjusting control agent
US7754739B2 (en) 2007-05-09 2010-07-13 Vertex Pharmaceuticals Incorporated Modulators of CFTR
US20080132560A1 (en) 2006-11-21 2008-06-05 San-Laung Chow Solid dispersion composition
WO2008065732A1 (en) 2006-11-27 2008-06-05 Nippon Polyurethane Industry Co., Ltd. Process for production of modified isocyanate mixture containing allophanate bond and isocyanurate bond
US20080260820A1 (en) 2007-04-19 2008-10-23 Gilles Borrelly Oral dosage formulations of protease-resistant polypeptides
US8969386B2 (en) 2007-05-09 2015-03-03 Vertex Pharmaceuticals Incorporated Modulators of CFTR
CN101687883B (en) 2007-05-25 2012-05-23 沃泰克斯药物股份有限公司 Modulators of cystic fibrosis transmembrane conductance regulator
US8557823B2 (en) 2007-06-18 2013-10-15 Advanced Cancer Therapeutics, Llc Family of PFKFB3 inhibitors with anti-neoplastic activities
WO2008156783A2 (en) 2007-06-18 2008-12-24 University Of Louisville Research Foundation, Inc. Family of pfkfb3 inhibitors with anti-neoplastic activities
ES2551095T3 (en) 2007-07-19 2015-11-16 Lundbeck, H., A/S 5-membered heterocyclic amides and related compounds
US20110177999A1 (en) 2007-08-09 2011-07-21 Vertex Pharmaceuticals Incorporated Therapeutic Combinations Useful in Treating CFTR Related Diseases
WO2009038913A2 (en) 2007-08-24 2009-03-26 Vertex Pharmaceuticals Incorporated Isothiazolopyridinones useful for the treatment of (inter alia) cystic fibrosis
JP5461405B2 (en) 2007-09-14 2014-04-02 バーテックス ファーマシューティカルズ インコーポレイテッド Regulators of cystic fibrosis membrane conductance regulator
NZ583848A (en) 2007-09-14 2012-07-27 Vertex Pharma Solid forms of n-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
WO2009055917A1 (en) 2007-11-02 2009-05-07 Methylgene Inc. Inhibitors of histone deacetylase
EP2217572B1 (en) 2007-11-16 2013-11-06 Vertex Pharmaceuticals Incorporated Isoquinoline modulators of atp-binding cassette transporters
EP2218718A1 (en) 2007-11-22 2010-08-18 Zenyaku Kogyo Kabushikikaisha Amorphous form of heterocyclic compound, solid dispersion and medicinal preparation each comprising the same, and process for production of the same
PL2225230T3 (en) 2007-12-07 2017-08-31 Vertex Pharmaceuticals Incorporated Solid forms of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl) benzoic acid
MX364936B (en) 2007-12-07 2019-05-15 Vertex Pharma Processes for producing cycloalkylcarboxiamido-pyridine benzoic acids.
US20100036130A1 (en) 2007-12-07 2010-02-11 Vertex Pharmaceuticals Incorporated Processes for producing cycloalkylcarboxamido-pyridine benzoic acids
EP2237768A2 (en) 2007-12-07 2010-10-13 Vertex Pharmaceuticals Incorporated Formulations of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
EP2231671B1 (en) 2007-12-13 2013-04-24 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US20090247521A1 (en) 2007-12-28 2009-10-01 Arete Therapeutics, Inc. Soluble epoxide hydrolase inhibitors for the treatment of endothelial dysfunction
ES2647531T3 (en) 2008-02-28 2017-12-22 Vertex Pharmaceuticals Incorporated Heteroaryl derivatives as CFTR modulators
EP2271621B1 (en) 2008-03-31 2013-11-20 Vertex Pharmaceuticals Incorporated Pyridyl derivatives as cftr modulators
US20110071197A1 (en) 2008-04-16 2011-03-24 Peter Nilsson Bis-aryl compounds for use as medicaments
WO2009129501A1 (en) 2008-04-18 2009-10-22 Arete Therapeutics, Inc. Use of soluble epoxide hydrolase inhibitors in the treatment of smooth muscle disorders
PT2276485E (en) 2008-04-24 2014-10-20 Bristol Myers Squibb Co Use of epothilone d in treating tau-associated diseases including alzheimer's disease
US20110112193A1 (en) 2008-05-14 2011-05-12 Peter Nilsson Bis-aryl compounds for use as medicaments
US9447049B2 (en) 2010-03-01 2016-09-20 University Of Tennessee Research Foundation Compounds for treatment of cancer
US8822513B2 (en) 2010-03-01 2014-09-02 Gtx, Inc. Compounds for treatment of cancer
US20100256184A1 (en) 2008-08-13 2010-10-07 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administrations thereof
CA2733908C (en) 2008-08-13 2017-05-30 Vertex Pharmaceuticals Incorporated Pharmaceutical composition comprising a solid dispersion of n-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US8895781B2 (en) 2008-09-04 2014-11-25 Georgetown University Transition metal-catalyzed C—H amination using unactivated amines
AR073578A1 (en) 2008-09-15 2010-11-17 Priaxon Ag PIRROLIDIN-2-ONAS
AR073709A1 (en) 2008-09-29 2010-11-24 Vertex Pharma ACID DOSE UNITS 3- (6- (1- (2,2-DIFLUOROBENZENE (D) (1,3) DIOXOL-5-IL) CYCLOPROPANCARBOXAMIDE) -3-METHYLPIRIDIN-2-IL) BENZOIC
WO2010048149A2 (en) 2008-10-20 2010-04-29 Kalypsys, Inc. Heterocyclic modulators of gpr119 for treatment of disease
US20110257223A1 (en) * 2008-10-23 2011-10-20 Vertex Pharmaceuticals Incorporated Modulators of Cystic Fibrosis Transmembrane Conductance Regulator
ES2532138T3 (en) 2008-10-23 2015-03-24 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
TWI465449B (en) * 2008-10-23 2014-12-21 Vertex Pharma Modulators of cystic fibrosis transmembrane conductance regulator
EP2358680B1 (en) 2008-10-23 2013-03-20 Vertex Pharmaceuticals Incorporated Solid forms of n-(4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide
UA104876C2 (en) 2008-11-06 2014-03-25 Вертекс Фармасьютікалз Інкорпорейтед Modulators of atp-binding cassette transporters
ES2532753T3 (en) 2008-11-06 2015-03-31 Vertex Pharmaceuticals Incorporated Conveyor modulators of the ATP binding cassette
CA2743241A1 (en) 2008-11-27 2010-06-03 Boehringer Ingelheim International Gmbh 6,7,8,9-tetrahydro-5h-1,4,7,10a-tetraaza-cyclohept[f]indene derivatives, pharmaceutical compositions containing these compounds, their use and processes for preparing them
BRPI0922364A2 (en) 2008-12-03 2017-08-29 Presidio Pharmaceuticals Inc COMPOUND, PHARMACEUTICAL COMPOSITION AND USE OF A COMPOUND
US8367660B2 (en) 2008-12-30 2013-02-05 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US8946419B2 (en) 2009-02-23 2015-02-03 Mallinckrodt Llc (+)-6-hydroxy-morphinan or (+)-6-amino-morphinan derivatives
WO2010104307A2 (en) 2009-03-07 2010-09-16 주식회사 메디젠텍 Pharmaceutical compositions for treating or preventing diseases caused by the translocation of gsk3 from the cell nucleus to the cytoplasm, containing compounds for inhibiting the translocation of gsk3 from the cell nucleus to the cytoplasm
AU2010226393B2 (en) 2009-03-20 2016-08-11 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
PT2408750E (en) 2009-03-20 2015-10-15 Vertex Pharma Process for making modulators of cystic fibrosis transmembrane conductance regulator
GB0905641D0 (en) 2009-04-01 2009-05-13 Serodus As Compounds
DK2419429T3 (en) 2009-04-16 2014-06-23 Ct Nac De Investigaciones Oncológicas Cnio IMIDAZOPYRAZINES AS INHIBITORS OF PROTEIN CHINAS
WO2011005355A1 (en) 2009-05-07 2011-01-13 Achaogen, Inc. Combinations comprising a lpxc inhibitor and an antibiotic for use in the treatment of infections caused by gram-negative bacteria
CN105254557A (en) 2009-05-29 2016-01-20 拉夸里亚创药株式会社 Aryl substituted carboxamide derivatives as calcium or sodium channel blockers
EP2264012A1 (en) 2009-06-03 2010-12-22 Bayer CropScience AG Heteroarylamidines and their use as fungicides
KR101256018B1 (en) 2009-08-20 2013-04-18 한국과학기술연구원 1,3,6-Substituted indole derivatives having inhibitory activity for protein kinase
WO2011029832A1 (en) 2009-09-09 2011-03-17 Vifor (International) Ag Novel thiazol and oxazol hepcidine antagonists
CN102498112B (en) 2009-09-17 2015-05-20 沃泰克斯药物股份有限公司 Process for preparing azabicyclic compounds
US9334230B2 (en) 2009-09-18 2016-05-10 Nanyang Technological University Process of forming an amide
EP2490687A1 (en) 2009-10-22 2012-08-29 Vertex Pharmaceuticals Incorporated Compositions for treatment of cystic fibrosis and other chronic diseases
BR112012009583A2 (en) 2009-10-23 2015-09-29 Vertex Pharma process for preparing cystic fibrosis transmembrane conductance regulator modulators
MX2012004791A (en) 2009-10-23 2013-02-01 Vertex Pharma Solid forms of n-(4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-trifluorom ethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-c arboxamide.
WO2011094890A1 (en) 2010-02-02 2011-08-11 Argusina Inc. Phenylalanine derivatives and their use as non-peptide glp-1 receptor modulators
RU2581367C2 (en) 2010-03-01 2016-04-20 Джи Ти Икс, ИНК. Compounds for treating cancer
WO2011115892A1 (en) 2010-03-15 2011-09-22 Griffin Patrick R Modulators of the retinoic acid receptor-related orphan receptors
EP3037415A1 (en) 2010-03-19 2016-06-29 Vertex Pharmaceuticals Inc. Solid form of n-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US8802868B2 (en) * 2010-03-25 2014-08-12 Vertex Pharmaceuticals Incorporated Solid forms of (R)-1(2,2-difluorobenzo[D][1,3]dioxo1-5-yl)-N-(1-(2,3-dihydroxypropyl-6-fluoro-2-(1-hydroxy-2-methylpropan2-yl)-1H-Indol-5-yl)-Cyclopropanecarboxamide
RS61314B1 (en) * 2010-03-25 2021-02-26 Vertex Pharma Solid dispersion of amorphous form of (r)-1(2,2-difluorobenzo(d)(1,3)dioxol-5-yl)-n-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1h-indol-5-yl)-cyclopropanecarboxamide
RS54783B1 (en) 2010-04-07 2016-10-31 Vertex Pharma Solid forms of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
NZ602838A (en) 2010-04-07 2015-06-26 Vertex Pharma Pharmaceutical compositions of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid and administration thereof
WO2011133951A1 (en) 2010-04-22 2011-10-27 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions and administrations thereof
SG184987A1 (en) * 2010-04-22 2012-11-29 Vertex Pharma Process of producing cycloalkylcarboxamido-indole compounds
CA2796602A1 (en) * 2010-04-22 2011-10-27 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions and administrations thereof
NZ603044A (en) * 2010-04-22 2015-08-28 Vertex Pharma Pharmaceutical compositions comprising cftr modulators and administrations thereof
EP2386606B1 (en) 2010-04-30 2018-03-21 Total Marketing Services Use of organogelator derivatives in bituminous compositions to improve the resistance thereof to chemical attacks
EP2571506B1 (en) 2010-05-20 2017-05-10 Cempra Pharmaceuticals, Inc. Processes for preparing macrolides and ketolides and intermediates therefor
WO2011146886A1 (en) 2010-05-20 2011-11-24 Vertex Pharmaceuticals Incorporated Processes for producing modulators of cystic fibrosis transmembrane conductance regulator
CA2798412A1 (en) 2010-05-20 2011-11-24 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions and administrations thereof
US8563593B2 (en) * 2010-06-08 2013-10-22 Vertex Pharmaceuticals Incorporated Formulations of (R)-1-(2,2-difluorobenzo[D] [1,3] dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide
US20120149708A1 (en) 2010-06-17 2012-06-14 George Mason University Modulators of viral transcription, and methods and compositions therewith
UA110113C2 (en) 2010-07-29 2015-11-25 BICYCLIC AZAGETEROCYCLIC CARBOXAMIDES
WO2012016133A2 (en) 2010-07-29 2012-02-02 President And Fellows Of Harvard College Ros1 kinase inhibitors for the treatment of glioblastoma and other p53-deficient cancers
CA2808501A1 (en) * 2010-08-23 2012-03-01 Vertex Pharmaceuticals Incorporated Pharmaceutical composition of (r)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-n-(1-(2,3-dihydroxy propyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1h-indol-5-yl) cyclopropanecarboxamide and administration therof
MX2013002353A (en) 2010-08-27 2013-09-26 Vertex Pharma Pharmaceutical composition and administrations thereof.
WO2012049555A1 (en) 2010-10-13 2012-04-19 Lupin Limited Spirocyclic compounds as voltage-gated sodium channel modulators
WO2012052540A1 (en) 2010-10-21 2012-04-26 Universitaet Des Saarlandes Selective cyp11b1 inhibitors for the treatment of cortisol dependent diseases
US8802700B2 (en) 2010-12-10 2014-08-12 Vertex Pharmaceuticals Incorporated Modulators of ATP-Binding Cassette transporters
WO2012079583A1 (en) 2010-12-15 2012-06-21 Aarhus Universitet System providing controlled delivery of gaseous co for carbonylation reactions
CA2827392A1 (en) 2011-02-24 2012-08-30 Emory University Noggin blocking compositions for ossification and methods related thereto
WO2012129562A2 (en) 2011-03-24 2012-09-27 The Scripps Research Institute Compounds and methods for inducing chondrogenesis
CN102731492B (en) 2011-03-30 2016-06-29 江苏恒瑞医药股份有限公司 Cyclohexanes derivant, its preparation method and in application pharmaceutically
HUE047354T2 (en) 2011-05-18 2020-04-28 Vertex Pharmaceuticals Europe Ltd Deuterated derivatives of ivacaftor
US8945605B2 (en) 2011-06-07 2015-02-03 Parion Sciences, Inc. Aerosol delivery systems, compositions and methods
WO2013005057A1 (en) 2011-07-07 2013-01-10 Centro Nacional De Investigaciones Oncológicas (Cnio) New compounds
BR112014005286B1 (en) 2011-09-09 2022-08-23 Lantheus Medical Imaging, Inc COMPOUNDS OF A FIRST AND A SECOND IMAGING AGENT TO DETERMINE INCOMPATIBILITY OF INNERVATION AND PERFUSION ON THE PART OF THE INDIVIDUAL
WO2013038373A1 (en) 2011-09-16 2013-03-21 Novartis Ag Pyridine amide derivatives
WO2013038381A1 (en) 2011-09-16 2013-03-21 Novartis Ag Pyridine/pyrazine amide derivatives
WO2013038386A1 (en) 2011-09-16 2013-03-21 Novartis Ag Heterocyclic compounds for the treatment of cystic fibrosis
JP6165733B2 (en) 2011-09-16 2017-07-19 ノバルティス アーゲー N-substituted heterocyclylcarboxamides
WO2013038378A1 (en) 2011-09-16 2013-03-21 Novartis Ag Pyridine amide derivatives
GB201116559D0 (en) 2011-09-26 2011-11-09 Univ Leuven Kath Novel viral replication inhibitors
CA2853299A1 (en) 2011-11-02 2013-05-10 Vertex Pharmaceuticals Incorporated Use of (n-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide) for treating cftr mediated diseases
MX357328B (en) * 2011-11-08 2018-07-05 Vertex Pharma Modulators of atp-binding cassette transporters.
US20140127901A1 (en) * 2012-11-08 2014-05-08 Taiwan Semiconductor Manufacturing Company, Ltd. Low-k damage free integration scheme for copper interconnects
WO2013086131A1 (en) 2011-12-06 2013-06-13 The Trustees Of The University Of Pennsylvania Inhibitors targeting drug-resistant influenza a
US8772541B2 (en) 2011-12-15 2014-07-08 University of Pittsburgh—of the Commonwealth System of Higher Education Cannabinoid receptor 2 (CB2) inverse agonists and therapeutic potential for multiple myeloma and osteoporosis bone diseases
EP2606726A1 (en) 2011-12-21 2013-06-26 Bayer CropScience AG N-Arylamidine-substituted trifluoroethylsulfide derivatives as acaricides and insecticides
KR20140117612A (en) 2012-01-25 2014-10-07 버텍스 파마슈티칼스 인코포레이티드 Formulations of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
EP2819670A1 (en) 2012-02-27 2015-01-07 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administration thereof
JP2015518504A (en) 2012-04-03 2015-07-02 スリーエム イノベイティブ プロパティズ カンパニー Crosslinkable composition containing photobase generator
US8674108B2 (en) 2012-04-20 2014-03-18 Vertex Pharmaceuticals Incorporated Solid forms of N-[2,4-bis(1,1-dimethylethy)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US9528016B2 (en) 2012-04-26 2016-12-27 Xerox Corporation Phase change inks comprising crystalline amides
US8888905B2 (en) 2012-04-26 2014-11-18 Xerox Corporation Fast crystallizing crystalline-amorphous ink compositions and methods for making the same
CA2813472A1 (en) 2012-04-26 2013-10-26 Xerox Corporation Rapid solidifying crystalline-amorphous inks
US9228101B2 (en) 2012-04-26 2016-01-05 Xerox Corporation Rapidly crystallizing phase change inks and methods for forming the same
US20130284054A1 (en) 2012-04-26 2013-10-31 Xerox Corporation Rapid solidifying crystalline-amorphous inks
GB2502624A (en) 2012-06-01 2013-12-04 Univ East Anglia Phosphoramide and phosphoramide-based catalysts and their use in intermolecular aziridination
EP2859005B1 (en) 2012-06-08 2018-10-31 Massachusetts Institute of Technology Phosphine-ligated palladium sulfonate palladacycles
AU2013270681A1 (en) * 2012-06-08 2014-12-18 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions for the treatment of CFTR -mediated disorders
FR2992317B1 (en) 2012-06-22 2016-05-13 Diverchim PROCESS FOR THE PREPARATION OF CHIRAL PEPTIDES
WO2014002106A1 (en) 2012-06-25 2014-01-03 Cadila Healthcare Limited Novel compounds for the treatment of dyslipidemia and related diseases
NZ703824A (en) 2012-07-12 2018-06-29 Proqr Therapeutics Ii Bv Oligonucleotides for making a change in the sequence of a target rna molecule present in a living cell
WO2014011050A1 (en) 2012-07-12 2014-01-16 Proqr Therapeutics B.V. Exon replacement with stabilized artificial rnas
AU2013290444B2 (en) 2012-07-16 2018-04-26 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions of (R)-1-(2,2-diflurorbenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl) cyclopropanecarboxamide and administration thereof
US10207989B2 (en) 2012-09-20 2019-02-19 Temple University—Of the Commonwealth System of Higher Education Substituted alkyl diaryl derivatives, methods of preparation and uses
WO2014068893A1 (en) 2012-10-29 2014-05-08 コニカミノルタ株式会社 Phase difference film, circularly polarizing plate, and image forming device
HRP20181740T4 (en) 2012-11-02 2024-01-05 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions for the treatment of cftr mediated diseases
US9757379B2 (en) 2012-11-14 2017-09-12 The Board Of Regents Of The University Of Texas System Inhibition of HIF-2α heterodimerization with HIF1β (ARNT)
JP6146990B2 (en) 2012-11-16 2017-06-14 コンサート ファーマシューティカルズ インコーポレイテッド Deuterated CFTR enhancer
SG11201503959VA (en) 2012-11-20 2015-06-29 Merial Inc Anthelmintic compounds and compositions and method of using thereof
ITMI20122065A1 (en) 2012-12-03 2014-06-04 Univ Padova USE OF CFTR CORRECTORS IN THE TREATMENT OF STRUCTURAL MUSCLE PATHOLOGIES
EP2929346A1 (en) 2012-12-05 2015-10-14 Institut National de la Santé et de la Recherche Médicale (INSERM) Diagnosis of cystic fibrosis
US20140158127A1 (en) 2012-12-07 2014-06-12 Parion Sciences, Inc. Nasal cannula for delivery of aerosolized medicaments
US20140221424A1 (en) 2013-01-30 2014-08-07 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions for use in the treatment of cystic fibrosis
US9452139B2 (en) 2013-03-14 2016-09-27 Novartis Ag Respirable agglomerates of porous carrier particles and micronized drug
US20140296164A1 (en) 2013-03-29 2014-10-02 Calista Therapeutics, Inc. Compositions and methods of use for cell targeted inhibitors of the Cystic Fibrosis transmembrane regulator associated ligand
AU2014264936B2 (en) 2013-05-07 2018-09-27 Galapagos Nv Novel compounds and pharmaceutical compositions thereof for the treatment of cystic fibrosis
AU2014268477A1 (en) 2013-05-24 2015-11-12 The California Institute For Biomedical Research Compounds for treatment of drug resistant and persistent tuberculosis
JP2014232188A (en) 2013-05-29 2014-12-11 コニカミノルタ株式会社 Cellulose acylate film, circularly polarizing plate and image display device
AU2014302458A1 (en) 2013-06-26 2015-12-24 Proteostasis Therapeutics, Inc. Methods of modulating CFTR activity
DK3030568T3 (en) 2013-08-08 2019-01-07 Galapagos Nv THIENO [2,3-C] PYRANES AS CFTR MODULATORS
US9688990B2 (en) 2013-09-12 2017-06-27 Institut National De La Sante Et De La Recherche Medicale (Inserm) Methods and pharmaceutical compositions for treatment of cystic fibrosis
JP6564380B2 (en) 2013-09-20 2019-08-21 ユニバーシティ オブ ピッツバーグ − オブ ザ コモンウェルス システム オブ ハイヤー エデュケイション Compounds for treating prostate cancer
EP3052190A4 (en) 2013-10-01 2017-07-19 New York University Amino, amido, and heterocyclic compounds as modulators of rage activity and uses thereof
US9700881B2 (en) 2013-10-09 2017-07-11 Emory University Heterocyclic coupling catalysts and methods related thereto
MX2016006118A (en) 2013-11-12 2016-07-21 Vertex Pharma Process of preparing pharmaceutical compositions for the treatment of cftr mediated diseases.
KR20150062652A (en) 2013-11-29 2015-06-08 삼성전자주식회사 Sonosensitive liposome, a pharmaceutical composition comprising the same and a method of delivering an active agent into a subject using the same
JP6759100B2 (en) 2013-12-30 2020-09-23 ライフサイ ファーマシューティカルズ，インク． Therapeutic inhibitor compound
US20170029366A1 (en) 2014-03-07 2017-02-02 The Johns Hopkins University Inhibitors of histone lysine specific demethylase (lsd1) and histone deacetylases (hdacs)
JP2015172005A (en) 2014-03-11 2015-10-01 国立大学法人 東京大学 Method of producing coupling compound by iron catalyst
US9790219B2 (en) 2014-03-13 2017-10-17 Proteostasis Therapeutics, Inc. Compounds, compositions, and methods for increasing CFTR activity
WO2015138934A1 (en) 2014-03-13 2015-09-17 Proteostasis Therapeutics, Inc. Compounds, compositions, and methods for increasing cftr activity
US10206877B2 (en) 2014-04-15 2019-02-19 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions for the treatment of cystic fibrosis transmembrane conductance regulator mediated diseases
JP5932881B2 (en) * 2014-05-08 2016-06-08 株式会社フジクラ Multi-core fiber and method for producing the multi-core fiber
AU2015255752B2 (en) 2014-05-08 2020-07-23 Immunoforge Co., Ltd. Methods and compositions for treating Cystic Fibrosis
RU2688191C2 (en) 2014-05-12 2019-05-21 ВЕРОНА ФАРМА ПиэЛСи New treatment
MY199033A (en) 2014-05-16 2023-10-10 Olaplex Inc Keratin treatment formulations and methods
WO2015179414A1 (en) 2014-05-19 2015-11-26 Merial, Inc. Anthelmintic compounds
AR100724A1 (en) 2014-06-05 2016-10-26 Merck Patent Gmbh DERIVATIVES OF QUINOLINA AND ITS USE IN NEURODEGENERATIVE DISEASES
WO2015196071A1 (en) 2014-06-19 2015-12-23 Proteostasis Therapeutics, Inc. Compounds, compositions and methods of increasing cftr activity
CN107105749A (en) 2014-08-13 2017-08-29 阿克索生物医药公司 Antimicrobe compound and composition and application thereof
GB201415381D0 (en) 2014-08-29 2014-10-15 Algipharma As Inhalable powder formulations of alginate oligomers
JP2017538659A (en) 2014-09-10 2017-12-28 エピザイム インコーポレイテッド SMYD inhibitor
WO2016050209A1 (en) 2014-10-01 2016-04-07 厦门赛诺邦格生物科技有限公司 Heterofunctionalized polyethylene glycol derivative, preparation method, and bio-related substance
WO2016050208A1 (en) 2014-10-01 2016-04-07 厦门赛诺邦格生物科技有限公司 Bio-related substance modified by multifunctionalized polyethylene glycol derivative
US11324827B2 (en) 2014-10-01 2022-05-10 Xiamen Sinopeg Biotech Co., Ltd. Multifunctionalized polyethylene glycol derivative and preparation method therefor
CN104725628B (en) 2014-10-01 2018-04-17 厦门赛诺邦格生物科技股份有限公司 A kind of single functionalization branched polyethylene glycol, preparation method and its bio-related substance containing degradable group
WO2016054560A1 (en) 2014-10-02 2016-04-07 Flatley Discovery Lab Isoxazole compounds and methods for the treatment of cystic fibrosis
US9573948B2 (en) 2014-10-06 2017-02-21 Flatley Discovery Lab Triazolopyridine compounds and methods for the treatment of cystic fibrosis
TWI735416B (en) 2014-10-06 2021-08-11 美商維泰克斯製藥公司 Modulators of cystic fibrosis transmembrane conductance regulator
RU2749213C2 (en) 2014-10-07 2021-06-07 Вертекс Фармасьютикалз Инкорпорейтед Co-crystals of transmembrane conduction regulator modulators in cystic fibrosis
US20170281612A1 (en) 2014-10-08 2017-10-05 Nivalis Therapeutics, Inc. Methods for the Treatment of Cystic Fibrosis
US20160108406A1 (en) 2014-10-08 2016-04-21 University Of Iowa Research Foundation Method of regulating cftr expression and processing
GB201418892D0 (en) 2014-10-23 2014-12-10 Proqr Therapeutics B V DNA editing
WO2016066582A1 (en) 2014-10-28 2016-05-06 Bci Pharma Nucleoside kinase inhibitors
EP3212189B1 (en) 2014-10-31 2020-09-09 AbbVie Overseas S.à r.l. Substituted chromanes and method of use
BR112017009194A2 (en) 2014-10-31 2017-12-26 Abbvie Sarl substituted tetrahydropyran and method of use
WO2016086015A1 (en) 2014-11-25 2016-06-02 University Of Rochester Myoglobin-based catalysts for carbene transfer reactions
MA41031A (en) 2014-11-26 2017-10-03 Catabasis Pharmaceuticals Inc CYSTEAMINE-FATTY ACID CONJUGATES AND THEIR USE AS AUTOPHAGIC ACTIVATORS
WO2016086136A1 (en) 2014-11-26 2016-06-02 Catabasis Pharmaceuticals, Inc. Fatty acid cysteamine conjugates of cftr modulators and their use in treating medical disorders
US10344023B2 (en) 2014-12-23 2019-07-09 Proteostasis Therapeutics, Inc. Derivatives of 3-heteroarylisoxazol-5-carboxylic amide useful for the treatment of inter alia cystic fibrosis
MA41253A (en) 2014-12-23 2017-10-31 Proteostasis Therapeutics Inc COMPOUNDS, COMPOSITIONS AND PROCESSES TO INCREASE THE ACTIVITY OF CFTR
CA2971850A1 (en) 2014-12-23 2016-06-30 Proteostasis Therapeutics, Inc. Derivatives of 5-phenyl- or 5-heteroarylthiazol-2-carboxylic amide useful for the treatment of inter alia cystic fibrosis
US10738011B2 (en) 2014-12-23 2020-08-11 Proteostasis Therapeutics, Inc. Derivatives of 5-(hetero)arylpyrazol-3-carboxylic amide or 1-(hetero)aryltriazol-4-carboxylic amide useful for the treatment of inter alia cystic fibrosis
ES2737227T3 (en) 2014-12-24 2020-01-10 Kither Biotech S R L Novel PI3K gamma inhibitor peptide for the treatment of diseases of the respiratory system
EP3240539A4 (en) 2014-12-31 2018-07-25 Auspex Pharmaceuticals, Inc. Cyclopropanecarboxamide modulators of cystic fibrosis transmembrane conductance regulator
WO2016107603A1 (en) 2015-01-01 2016-07-07 成都贝斯凯瑞生物科技有限公司 Substituted nitrogen-containing heterocyclic derivatives and applications thereof
US20180147187A1 (en) 2015-01-12 2018-05-31 Proteostasis Therapeutics, Inc. Compounds, compositions, and methods for increasing cftr activity
CA2981495C (en) 2015-03-31 2023-09-26 Vertex Pharmaceuticals (Europe) Limited Deuterated vx-661

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002012236A1 (en) * 2000-08-04 2002-02-14 Bayer Cropscience Ag Substituted triazolopyrid(az)ines as plant treatment agents (herbicides)
WO2002011883A1 (en) * 2000-08-07 2002-02-14 Yale University CATALYST FOR AROMATIC C-O, C-N, and C-C BOND FORMATION
EP1864978A1 (en) * 2005-03-28 2007-12-12 Toyama Chemical Co., Ltd. Process for production of 1-(3-(2-(1-benzothiophen-5-yl)- ethoxy)propyl)azetidin-3-ol or salts thereof
US20090131492A1 (en) * 2006-04-07 2009-05-21 Ruah Sara S Hadida Indole derivatives as CFTR modulators

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BEARE ET AL: "Palladium-CatalyzedArylation of Malonates and Cyano Esters Using Sterically Hindered Trialkyl- and Ferrocenyldialkylphosphine Ligands" JOURNAL OF ORGANIC CHEMISTRY, vol. 67, 1 January 2002, pages 541-555 *
STAUFFER SHAUN R ET AL:" Palladium-Catalyzed Arylation of Ethyl Cyanoacetate. Fluorescence Resonance Energy Transfer as a Tool for Reaction Discovery" JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol . 123, no. 19, 1 Jan 2001, pages 4641-4642 *
SUZUKI ET AL." A simple one-pot conversion of aryl halides into arylacetonitriles" CHEMISTRY LETTERS, 1983, pages 193-194 *

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